ABCMdb

PMID: 11527935

Briggs CE, Rucinski D, Rosenfeld PJ, Hirose T, Berson EL, Dryja TP
Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration.
Invest Ophthalmol Vis Sci. 2001 Sep;42(10):2229-36., [PubMed]

Sentences

No. Mutations Sentence Comment

10 ABCA4 p.Ile824Thr The authors found one instance of an apparently de novo mutation, Ile824Thr, in a patient. Login to comment 56 ABCA4 p.Met1Val Twenty-one of the changes (including 15 novel changes) were interpreted as obviously null mutations: One was a missense change affecting the initiation codon (Met1Val), four were nonsense mutations, four changed canonical splice-site donor or acceptor sites, and 12 were frameshifts caused by the insertion or deletion of one or more base pairs (Table 1). Login to comment 57 ABCA4 p.Met1Val Twenty-one of the changes (including 15 novel changes) were interpreted as obviously null mutations: One was a missense change affecting the initiation codon (Met1Val), four were nonsense mutations, four changed canonical splice-site donor or acceptor sites, and 12 were frameshifts caused by the insertion or deletion of one or more base pairs (Table 1). Login to comment 62 ABCA4 p.Gly1961Glu ABCA4 p.Leu541Pro ABCA4 p.Leu2027Phe ABCA4 p.Pro1380Leu Specifically, Leu541Pro, Pro1380Leu, Gly1961Glu, and Leu2027Phe were not identified in any of the control individuals (P b0d; 0.04). Login to comment 63 ABCA4 p.Gly1961Glu ABCA4 p.Gly863Ala ABCA4 p.Leu541Pro ABCA4 p.Leu2027Phe ABCA4 p.Pro1380Leu Specifically, Leu541Pro, Pro1380Leu, Gly1961Glu, and Leu2027Phe were not identified in any of the control individuals (P Ͻ 0.04). Login to comment 64 ABCA4 p.Gly863Ala ABCA4 p.Arg212His ABCA4 p.Pro1948Leu ABCA4 p.Arg943Gln ABCA4 p.His423Arg Gly863Ala was detected in 9 of 252 patient alleles and 2 of 380 normal control alleles tested (P ϭ 0.009), and it was also considered pathogenic. Login to comment 65 ABCA4 p.Arg212His ABCA4 p.Asn1868Ile ABCA4 p.Pro1948Leu ABCA4 p.Arg943Gln ABCA4 p.His423Arg Four missense changes, Arg212His, His423Arg, Arg943Gln, and Pro1948Leu, were found at approximately equal frequency among patients and normal control subjects (P Ͼ 0.05 by Fisher`s two-tailed analysis) and were thus categorized as nonpathogenic polymorphisms. Login to comment 66 ABCA4 p.Asn1868Ile Asn1868Ile was less frequent in patients with Stargardt disease than in control subjects (42/252 patient alleles and 50/170 control alleles; P ϭ 0.002 by Fisher`s two-tailed analysis) and was therefore considered nonpathogenic. Login to comment 67 ABCA4 p.Ala1637Thr A rarely encountered missense change, Ala1637Thr, was interpreted as nonpathogenic because it was found in a patient (032-066) who also had two obviously null mutations determined to be allelic by segregation analysis, Lys356Ter and Gln1513(insC). Login to comment 68 ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Ala1637Thr A rarely encountered missense change, Ala1637Thr, was interpreted as nonpathogenic because it was found in a patient (032-066) who also had two obviously null mutations determined to be allelic by segregation analysis, Lys356Ter and Gln1513(insC). Login to comment 69 ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro Another change, Ala1038Val, was found in two patients (032-023 and 034-035), and in both cases segregation analysis showed that it was in cis with Leu541Pro, a combination also reported by Rivera et al.23 We interpreted Leu541Pro as pathogenic because it was found without the Ala1038Val change more frequently in patients than in control subjects. Login to comment 70 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro However, Sun et al.26 have shown abnormal ABCR function associated with either Ala1038Val or Leu541Pro, and it is therefore possible that both these changes are pathogenic in isolation. Login to comment 80 ABCA4 p.Arg1640Gln ABCA4 p.Pro1380Leu ABCA4 p.Cys2150Tyr ABCA4 p.Leu244Pro An additional three with Stargardt and two with CRD were homozygotes for a likely pathogenic sequence change (Leu244Pro, Pro1380Leu, Arg1640Gln, Cys2150Tyr, or Val1973[delG]). Login to comment 81 ABCA4 p.Arg1640Gln ABCA4 p.Pro1380Leu ABCA4 p.Cys2150Tyr ABCA4 p.Leu244Pro An additional three with Stargardt and two with CRD were homozygotes for a likely pathogenic sequence change (Leu244Pro, Pro1380Leu, Arg1640Gln, Cys2150Tyr, or Val1973[delG]). Login to comment 82 ABCA4 p.Gly1961Glu ABCA4 p.Ile824Thr One family had an index member (034-045) who was heterozygous for the missense changes Ile824Thr and Gly1961Glu. Login to comment 83 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ile824Thr ABCA4 p.Ile824Thr One family had an index member (034-045) who was heterozygous for the missense changes Ile824Thr and Gly1961Glu. Login to comment 84 ABCA4 p.Gly1961Glu ABCA4 p.Ile824Thr ABCA4 p.Ile824Thr The Gly1961Glu allele27 was found to have been inherited from the patient`s mother, but the Ile824Thr allele was not detected in either parent or in any sibling. Login to comment 85 ABCA4 p.Ile824Thr The results of genotyping analysis of six microsatellite markers in the patient and her parents were consistent with the designated paternity and we interpreted the Ile824Thr allele as a de novo mutation in this patient. Login to comment 86 ABCA4 p.Gly1961Glu ABCA4 p.Ile824Thr We did not conduct further studies to determine whether the Ile824Thr and Gly1961Glu changes were allelic in this index patient. Login to comment 87 ABCA4 p.Gly1961Glu ABCA4 p.Ile824Thr We did not conduct further studies to determine whether the Ile824Thr and Gly1961Glu changes were allelic in this index patient. Login to comment 88 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Arg1640Trp ABCA4 p.Arg1640Trp ABCA4 p.Gly1977Ser ABCA4 p.Cys1488Arg ABCA4 p.Cys54Tyr ABCA4 p.Cys54Tyr ABCA4 p.Cys54Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Arg2139Trp ABCA4 p.Val989Ala ABCA4 p.Val989Ala ABCA4 p.Arg1640Gln ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Ile1562Thr ABCA4 p.Val767Asp ABCA4 p.Val767Asp ABCA4 p.Cys2150Arg ABCA4 p.Arg1108Cys ABCA4 p.Val935Ala ABCA4 p.Val935Ala ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1486Leu ABCA4 p.Pro1486Leu ABCA4 p.Pro1486Leu ABCA4 p.Pro309Arg ABCA4 p.Pro309Arg ABCA4 p.Leu1201Arg ABCA4 p.Val643Met ABCA4 p.Val643Met ABCA4 p.Arg1300Gln ABCA4 p.Arg1300Gln ABCA4 p.Arg1300Gln ABCA4 p.Arg1300Gln ABCA4 p.Arg1300Gln ABCA4 p.Trp1408Arg ABCA4 p.Trp1408Arg ABCA4 p.Ile1846Thr ABCA4 p.Ile1846Thr ABCA4 p.Arg602Gln ABCA4 p.Arg602Gln ABCA4 p.Arg537Cys ABCA4 p.Arg537Cys ABCA4 p.Arg537Cys ABCA4 p.Arg537Cys ABCA4 p.Ala549Pro ABCA4 p.Ala549Pro ABCA4 p.Gln190His ABCA4 p.Gln190His ABCA4 p.Asn58Lys ABCA4 p.Asn58Lys ABCA4 p.Arg943Trp ABCA4 p.Arg943Trp ABCA4 p.Arg2107Cys ABCA4 p.Arg1108Leu ABCA4 p.Pro1776Leu ABCA4 p.Pro1776Leu ABCA4 p.Leu1388Pro ABCA4 p.Leu1388Pro ABCA4 p.Leu797Pro ABCA4 p.Leu797Pro ABCA4 p.Phe525Cys ABCR Sequence Changes Found in 118 Patients with Stargardt and 8 with CRD Patient ID Mutations (Amino Acid Based) Sequence Change (Nucleotide Based) Het/Hom Other Sequence Changes 21 Null Mutations 071-004 Met1Val ATG 3 GTC Het None 035-002* Ser84(insCAAA)30 251ins4 Het IVS36 af9; 1G 3 A 034-039 Ser84(insCAAA)30 251ins4 Het Gly1961Glu 032-018 Arg152Ter23 CGA 3 TGA Het Arg2107Cys 032-005 Ala222(del13bp) 666del13 [AAAGACGGTGCGC] Het None 032-039 Ala222(del13bp) 666del13 [AAAGACGGTGCGC] Het None 032-060 [Ser278(delT); Arg1300Gln] [832delT; CGA 3 CAA] Het Pro1486Leu 032-066* Lys356Ter AAG 3 TAG Het Gln1513(insC) 032-072 - IVS13 af9; 2T 3 C Het Val77Glu 032-073 Arg681Ter21 CGA 3 TGA Het Leu1388Pro 034-016 Ser1071(insGT)31 3212insGT Het None 032-065 Ser1071(insGT)31 3212insGT Het None 035-003 Ile1114(delC)5 3340delC Het Pro1380Leu 007-014* - IVS26 af9; 1G 3 A Het Asn1345(insCA) 007-014* Asn1345(insCA) 4034insCA Het IVS26 af9; 1G 3 A 032-066* Gln1513(insC) 4538insC Het Lys356Ter 032-010 Gln1513(insC) 4538insC Het None 032-024 Pro1570(delC)16 4710delC Het Gly1961Glu 032-016 Thr1721 (delAC) delete AC @ nt 5161 Het Thr1525Met 035-002* - IVS36 af9; 1G 3 A23 Het Ser84(insCAAA) 034-031 Leu1741(del11) 5194del11 [GTGGTGGGCAT] Het Gly1961Glu 032-051 Trp1772Ter TGG 3 TGA Het None 032-022 - IVS41-2delA Het Gly1961Glu 032-081* Val1973(delG) 5917delG Hom None 034-017 Gly2100(delG) 6300delG Het Gly1961Glu 55 Missense and One In-Frame Deletion 032-020 Cys54Tyr15 TGC 3 TAC Het Gly863Ala 035-012 Cys54Tyr15 TGC 3 TAC Het Arg1108Cys 071-007 Cys54Tyr15 TGC 3 TAC Het Val935Ala 071-003 Asn58Lys AAC 3 AAG Het Leu1201Arg 032-069 Ala60Val15 GCG 3 GTG Het None 032-028 Gly65Glu16 GGA 3 GAA Het None 032-072 Val77Glu GTG 3 CAG Het IVS13 af9; 2T 3 C 034-013 Gln190His CAG 3 CAC Het Gly1961Glu 032-076 Leu244Pro CTG 3 CCG Hom None 032-012 Pro309Arg CCA 3 CGA Het Arg1300Gln 032-054 Phe525Cys TTT 3 TGT Het Ile1846Thr 032-046 Arg537Cys CGT 3 TGT Het Val989Ala 034-038 Arg537Cys CGT 3 TGT Het Gly863Ala 032-095 Leu541Pro18 CTA 3 CCA Het None 034-022 Leu541Pro18 CTA 3 CCA Het Leu2027Phe 035-001 Leu541Pro18 CTA 3 CCA Het None 032-009 Leu541Pro18 CTA 3 CCA Het None 032-023 [Leu541Pro18 ; Ala1038Val27 ] [CTA 3 CCA; GCC 3 GTC] Het Gly863Ala 034-035 [Leu541Pro18 ; Ala1038Val27 ] [CTA 3 CCA; GCC 3 GTC] Het Gly863Ala 032-011 Ala549Pro GCC 3 CCC Het Gly1961Glu 032-044 Gly550Arg GGA 3 AGA Het None 032-085 Arg602Gln CGG 3 CAG Het Val643Met 032-090 Gly607Arg GGG 3 AGG Het Leu2027Phe 032-085 Val643Met GTG 3 ATG Het Arg602Gln 032-042 Val767Asp30 GTC 3 GAG Het Pro1486Leu 071-006 Val767Asp30 GTC 3 GAG Het Ile1562Thr 032-014 Leu797Pro CTG 3 CCG Het Pro1486Leu 032-038 Trp821Arg18 TGG 3 AGG Het None 034-045 Ile824Thr ATC 3 ACC Het Gly1961Glu 032-056 Gly863Ala5 GGA 3 GCA Het None 032-091 Gly863Ala5 GGA 3 GCA Het None 032-020 Gly863Ala5 GGA 3 GCA Het Cys54Tyr 032-023 Gly863Ala5 GGA 3 GCA Het [Leu541Pro; Ala1038Val] 034-011 Gly863Ala5 GGA 3 GCA Het Cys1488Arg 034-015 Gly863Ala5 GGA 3 GCA Het Thr1525Met 034-035 Gly863Ala5 GGA 3 GCA Het [Leu541Pro; Ala1038Val] 034-036 Gly863Ala5 GGA 3 GCA Het Cys2150Arg 034-038 Gly863Ala5 GGA 3 GCA Het Arg537Cys 071-007 Val935Ala GTA 3 GCA Het Cys54Tyr 032-043 Arg943Trp CGG 3 TGG Het Arg1108Leu 032-046 Val989Ala GTT 3 GCT Het Arg537Cys 071-005 Arg1108Cys18 CGC 3 TGC Het None IOVS, September 2001, Vol. 42, No. 10 ABCR in Stargardt Macular Degeneration Patient ID Mutations (Amino Acid Based) Sequence Change (Nucleotide Based) Het/Hom Other Sequence Changes 035-012 Arg1108Cys18 CGC 3 TGC Het Cys54Tyr 032-043 Arg1108Leu5 CGC 3 CTC Het Arg943Trp 032-097 Glu1122Lys18 GAG 3 AAG Het None 035-019 Glu1122Lys18 GAG 3 AAG Het None 071-003 Leu1201Arg15 CTG 3 CGG Het Asn58Lys 032-012 Arg1300Gln CGA 3 CAA Het Pro309Arg 032-068 Arg1300Gln CGA 3 CAA Het None 032-013 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 032-015 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 032-027 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 071-001 Pro1380Leu15 CCG 3 CTG Hom None 034-020 Pro1380Leu15 CCG 3 CTG Het Leu2027Phe 034-028 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 034-044 Pro1380Leu15 CCG 3 CTG Het Leu2027Phe 034-048 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 035-003 Pro1380Leu15 CCG 3 CTG Het Ile1114(delC) 032-073 Leu1388Pro CTG 3 CCG Het Arg681Ter 034-040 Trp1408Arg15 TGG 3 CGG Het Arg1640Trp 035-013 Trp1408Arg15 TGG 3 CGG Het Arg1640Trp 032-060 Pro1486Leu20 CCA 3 CTA Het [Ser278(delT); Arg1300Gln] 032-014 Pro1486Leu20 CCA 3 CTA Het Leu797Pro 032-025 Pro1486Leu20 CCA 3 CTA Het Asp1531Asn 032-042 Pro1486Leu20 CCA 3 CTA Het Val767Asp 034-011 Cys1488Arg15 TGC 3 CGC Het Gly863Ala 032-034 Cys1490Tyr15 TGC 3 TAC Het Ile1846Thr 032-084 Thr1525Met15 ACG 3 ATG Het Arg2139Trp 032-016 Thr1525Met15 ACG 3 ATG Het Thr1721(delAC) 032-021 Thr1525Met15 ACG 3 ATG Het None 032-041 Thr1525Met15 ACG 3 ATG Het None 034-015 Thr1525Met15 ACG 3 ATG Het Gly863Ala 032-049 Asp1531Asn15 GAC 3 AAC Het Gly1961Glu 034-019 Asp1531Asn15 GAC 3 AAC Het None 032-025 Asp1531Asn15 GAC 3 AAC Het Pro1846Leu 071-006 Ile1562Thr27 ATT 3 ACT Het Val767Asp 034-040 Arg1640Trp18 CGG 3 TGG Het Trp1408Arg 035-013 Arg1640Trp18 CGG 3 TGG Het Trp1408Arg 032-030* Arg1640Gln CGG 3 CAG Hom None 032-019 Pro1776Leu CCC 3 CTC Het Gly1961Glu 032-034 Ile1846Thr21 ATT 3 ACT Het Cys1490Tyr 032-054 Ile1846Thr21 ATT 3 ACT Het Phe525Cys 032-011 Gly1961Glu27 GGA 3 GAA Het Ala549Pro 032-013 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 032-015 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 032-019 Gly1961Glu27 GGA 3 GAA Het Pro1776Leu 032-022 Gly1961Glu27 GGA 3 GAA Het IVS41-2delA 032-024 Gly1961Glu27 GGA 3 GAA Het Pro1570(delC) 032-027 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 032-040 Gly1961Glu27 GGA 3 GAA Het None 032-049 Gly1961Glu27 GGA 3 GAA Het Asp1531Asn 034-013 Gly1961Glu27 GGA 3 GAA Het Gln190His 034-017 Gly1961Glu27 GGA 3 GAA Het Gly2100(delG) 034-021 Gly1961Glu27 GGA 3 GAA Het None 034-025 Gly1961Glu27 GGA 3 GAA Het None 034-028 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 034-031 Gly1961Glu27 GGA 3 GAA Het Leu1741(del11) 034-033 Gly1961Glu27 GGA 3 GAA Het None 034-039 Gly1961Glu27 GGA 3 GAA Het Ser84(insCAAA) 032-050 Gly1961Glu27 GGA 3 GAA Het None 034-045 Gly1961Glu27 GGA 3 GAA Het Ile824Thr 034-048 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 032-003 Gly1977Ser15 GGC 3 AGC Het Leu2027Phe 032-003 Leu2027Phe5 CTC 3 TTC Het Gly1977Ser 032-090 Leu2027Phe5 CTC 3 TTC Het Gly607Arg 034-006 Leu2027Phe5 CTC 3 TTC Het None 034-020 Leu2027Phe5 CTC 3 TTC Het Pro1380Leu 034-022 Leu2027Phe5 CTC 3 TTC Het Leu541Pro 034-044 Leu2027Phe5 CTC 3 TTC Het Pro1380Leu 035-011 Leu2027Phe5 CTC 3 TTC Het None 032-063 Arg2030Gln15 CGA 3 CAA Het None 032-093 Arg2030Gln15 CGA 3 CAA Het None 2232 Briggs et al. IOVS, September 2001, Vol. 42, No. 10 TABLE 1 (continued). Login to comment 89 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Arg1640Trp ABCA4 p.Arg1640Trp ABCA4 p.Gly1977Ser ABCA4 p.Cys1488Arg ABCA4 p.Cys54Tyr ABCA4 p.Cys54Tyr ABCA4 p.Cys54Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Arg2139Trp ABCA4 p.Arg2139Trp ABCA4 p.Val989Ala ABCA4 p.Val989Ala ABCA4 p.Arg1640Gln ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Ile1562Thr ABCA4 p.Val767Asp ABCA4 p.Val767Asp ABCA4 p.Cys2150Arg ABCA4 p.Cys2150Arg ABCA4 p.Arg1108Cys ABCA4 p.Val935Ala ABCA4 p.Val935Ala ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1486Leu ABCA4 p.Pro1486Leu ABCA4 p.Pro1486Leu ABCA4 p.Pro309Arg ABCA4 p.Pro309Arg ABCA4 p.Leu1201Arg ABCA4 p.Val643Met ABCA4 p.Val643Met ABCA4 p.Arg1300Gln ABCA4 p.Arg1300Gln ABCA4 p.Arg1300Gln ABCA4 p.Arg1300Gln ABCA4 p.Arg1300Gln ABCA4 p.Trp1408Arg ABCA4 p.Trp1408Arg ABCA4 p.Ile1846Thr ABCA4 p.Ile1846Thr ABCA4 p.Arg602Gln ABCA4 p.Arg602Gln ABCA4 p.Arg537Cys ABCA4 p.Arg537Cys ABCA4 p.Arg537Cys ABCA4 p.Arg537Cys ABCA4 p.Leu2035Pro ABCA4 p.Gly2146Asp ABCA4 p.Ala1637Thr ABCA4 p.Ala549Pro ABCA4 p.Ala549Pro ABCA4 p.Gln190His ABCA4 p.Asn58Lys ABCA4 p.Asn58Lys ABCA4 p.Arg943Trp ABCA4 p.Arg943Trp ABCA4 p.Arg2107Cys ABCA4 p.Arg2107Cys ABCA4 p.Arg1108Leu ABCA4 p.Pro1776Leu ABCA4 p.Pro1776Leu ABCA4 p.Leu1388Pro ABCA4 p.Leu1388Pro ABCA4 p.Leu797Pro ABCA4 p.Leu797Pro ABCR Sequence Changes Found in 118 Patients with Stargardt and 8 with CRD Patient ID Mutations (Amino Acid Based) Sequence Change (Nucleotide Based) Het/Hom Other Sequence Changes 21 Null Mutations 071-004 Met1Val ATG 3 GTC Het None 035-002* Ser84(insCAAA)30 251ins4 Het IVS36 ϩ 1G 3 A 034-039 Ser84(insCAAA)30 251ins4 Het Gly1961Glu 032-018 Arg152Ter23 CGA 3 TGA Het Arg2107Cys 032-005 Ala222(del13bp) 666del13 [AAAGACGGTGCGC] Het None 032-039 Ala222(del13bp) 666del13 [AAAGACGGTGCGC] Het None 032-060 [Ser278(delT); Arg1300Gln] [832delT; CGA 3 CAA] Het Pro1486Leu 032-066* Lys356Ter AAG 3 TAG Het Gln1513(insC) 032-072 - IVS13 ϩ 2T 3 C Het Val77Glu 032-073 Arg681Ter21 CGA 3 TGA Het Leu1388Pro 034-016 Ser1071(insGT)31 3212insGT Het None 032-065 Ser1071(insGT)31 3212insGT Het None 035-003 Ile1114(delC)5 3340delC Het Pro1380Leu 007-014* - IVS26 ϩ 1G 3 A Het Asn1345(insCA) 007-014* Asn1345(insCA) 4034insCA Het IVS26 ϩ 1G 3 A 032-066* Gln1513(insC) 4538insC Het Lys356Ter 032-010 Gln1513(insC) 4538insC Het None 032-024 Pro1570(delC)16 4710delC Het Gly1961Glu 032-016 Thr1721 (delAC) delete AC @ nt 5161 Het Thr1525Met 035-002* - IVS36 ϩ 1G 3 A23 Het Ser84(insCAAA) 034-031 Leu1741(del11) 5194del11 [GTGGTGGGCAT] Het Gly1961Glu 032-051 Trp1772Ter TGG 3 TGA Het None 032-022 - IVS41-2delA Het Gly1961Glu 032-081* Val1973(delG) 5917delG Hom None 034-017 Gly2100(delG) 6300delG Het Gly1961Glu 55 Missense and One In-Frame Deletion 032-020 Cys54Tyr15 TGC 3 TAC Het Gly863Ala 035-012 Cys54Tyr15 TGC 3 TAC Het Arg1108Cys 071-007 Cys54Tyr15 TGC 3 TAC Het Val935Ala 071-003 Asn58Lys AAC 3 AAG Het Leu1201Arg 032-069 Ala60Val15 GCG 3 GTG Het None 032-028 Gly65Glu16 GGA 3 GAA Het None 032-072 Val77Glu GTG 3 CAG Het IVS13 ϩ 2T 3 C 034-013 Gln190His CAG 3 CAC Het Gly1961Glu 032-076 Leu244Pro CTG 3 CCG Hom None 032-012 Pro309Arg CCA 3 CGA Het Arg1300Gln 032-054 Phe525Cys TTT 3 TGT Het Ile1846Thr 032-046 Arg537Cys CGT 3 TGT Het Val989Ala 034-038 Arg537Cys CGT 3 TGT Het Gly863Ala 032-095 Leu541Pro18 CTA 3 CCA Het None 034-022 Leu541Pro18 CTA 3 CCA Het Leu2027Phe 035-001 Leu541Pro18 CTA 3 CCA Het None 032-009 Leu541Pro18 CTA 3 CCA Het None 032-023 [Leu541Pro18 ; Ala1038Val27 ] [CTA 3 CCA; GCC 3 GTC] Het Gly863Ala 034-035 [Leu541Pro18 ; Ala1038Val27 ] [CTA 3 CCA; GCC 3 GTC] Het Gly863Ala 032-011 Ala549Pro GCC 3 CCC Het Gly1961Glu 032-044 Gly550Arg GGA 3 AGA Het None 032-085 Arg602Gln CGG 3 CAG Het Val643Met 032-090 Gly607Arg GGG 3 AGG Het Leu2027Phe 032-085 Val643Met GTG 3 ATG Het Arg602Gln 032-042 Val767Asp30 GTC 3 GAG Het Pro1486Leu 071-006 Val767Asp30 GTC 3 GAG Het Ile1562Thr 032-014 Leu797Pro CTG 3 CCG Het Pro1486Leu 032-038 Trp821Arg18 TGG 3 AGG Het None 034-045 Ile824Thr ATC 3 ACC Het Gly1961Glu 032-056 Gly863Ala5 GGA 3 GCA Het None 032-091 Gly863Ala5 GGA 3 GCA Het None 032-020 Gly863Ala5 GGA 3 GCA Het Cys54Tyr 032-023 Gly863Ala5 GGA 3 GCA Het [Leu541Pro; Ala1038Val] 034-011 Gly863Ala5 GGA 3 GCA Het Cys1488Arg 034-015 Gly863Ala5 GGA 3 GCA Het Thr1525Met 034-035 Gly863Ala5 GGA 3 GCA Het [Leu541Pro; Ala1038Val] 034-036 Gly863Ala5 GGA 3 GCA Het Cys2150Arg 034-038 Gly863Ala5 GGA 3 GCA Het Arg537Cys 071-007 Val935Ala GTA 3 GCA Het Cys54Tyr 032-043 Arg943Trp CGG 3 TGG Het Arg1108Leu 032-046 Val989Ala GTT 3 GCT Het Arg537Cys 071-005 Arg1108Cys18 CGC 3 TGC Het None Patient ID Mutations (Amino Acid Based) Sequence Change (Nucleotide Based) Het/Hom Other Sequence Changes 035-012 Arg1108Cys18 CGC 3 TGC Het Cys54Tyr 032-043 Arg1108Leu5 CGC 3 CTC Het Arg943Trp 032-097 Glu1122Lys18 GAG 3 AAG Het None 035-019 Glu1122Lys18 GAG 3 AAG Het None 071-003 Leu1201Arg15 CTG 3 CGG Het Asn58Lys 032-012 Arg1300Gln CGA 3 CAA Het Pro309Arg 032-068 Arg1300Gln CGA 3 CAA Het None 032-013 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 032-015 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 032-027 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 071-001 Pro1380Leu15 CCG 3 CTG Hom None 034-020 Pro1380Leu15 CCG 3 CTG Het Leu2027Phe 034-028 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 034-044 Pro1380Leu15 CCG 3 CTG Het Leu2027Phe 034-048 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 035-003 Pro1380Leu15 CCG 3 CTG Het Ile1114(delC) 032-073 Leu1388Pro CTG 3 CCG Het Arg681Ter 034-040 Trp1408Arg15 TGG 3 CGG Het Arg1640Trp 035-013 Trp1408Arg15 TGG 3 CGG Het Arg1640Trp 032-060 Pro1486Leu20 CCA 3 CTA Het [Ser278(delT); Arg1300Gln] 032-014 Pro1486Leu20 CCA 3 CTA Het Leu797Pro 032-025 Pro1486Leu20 CCA 3 CTA Het Asp1531Asn 032-042 Pro1486Leu20 CCA 3 CTA Het Val767Asp 034-011 Cys1488Arg15 TGC 3 CGC Het Gly863Ala 032-034 Cys1490Tyr15 TGC 3 TAC Het Ile1846Thr 032-084 Thr1525Met15 ACG 3 ATG Het Arg2139Trp 032-016 Thr1525Met15 ACG 3 ATG Het Thr1721(delAC) 032-021 Thr1525Met15 ACG 3 ATG Het None 032-041 Thr1525Met15 ACG 3 ATG Het None 034-015 Thr1525Met15 ACG 3 ATG Het Gly863Ala 032-049 Asp1531Asn15 GAC 3 AAC Het Gly1961Glu 034-019 Asp1531Asn15 GAC 3 AAC Het None 032-025 Asp1531Asn15 GAC 3 AAC Het Pro1846Leu 071-006 Ile1562Thr27 ATT 3 ACT Het Val767Asp 034-040 Arg1640Trp18 CGG 3 TGG Het Trp1408Arg 035-013 Arg1640Trp18 CGG 3 TGG Het Trp1408Arg 032-030* Arg1640Gln CGG 3 CAG Hom None 032-019 Pro1776Leu CCC 3 CTC Het Gly1961Glu 032-034 Ile1846Thr21 ATT 3 ACT Het Cys1490Tyr 032-054 Ile1846Thr21 ATT 3 ACT Het Phe525Cys 032-011 Gly1961Glu27 GGA 3 GAA Het Ala549Pro 032-013 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 032-015 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 032-019 Gly1961Glu27 GGA 3 GAA Het Pro1776Leu 032-022 Gly1961Glu27 GGA 3 GAA Het IVS41-2delA 032-024 Gly1961Glu27 GGA 3 GAA Het Pro1570(delC) 032-027 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 032-040 Gly1961Glu27 GGA 3 GAA Het None 032-049 Gly1961Glu27 GGA 3 GAA Het Asp1531Asn 034-013 Gly1961Glu27 GGA 3 GAA Het Gln190His 034-017 Gly1961Glu27 GGA 3 GAA Het Gly2100(delG) 034-021 Gly1961Glu27 GGA 3 GAA Het None 034-025 Gly1961Glu27 GGA 3 GAA Het None 034-028 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 034-031 Gly1961Glu27 GGA 3 GAA Het Leu1741(del11) 034-033 Gly1961Glu27 GGA 3 GAA Het None 034-039 Gly1961Glu27 GGA 3 GAA Het Ser84(insCAAA) 032-050 Gly1961Glu27 GGA 3 GAA Het None 034-045 Gly1961Glu27 GGA 3 GAA Het Ile824Thr 034-048 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 032-003 Gly1977Ser15 GGC 3 AGC Het Leu2027Phe 032-003 Leu2027Phe5 CTC 3 TTC Het Gly1977Ser 032-090 Leu2027Phe5 CTC 3 TTC Het Gly607Arg 034-006 Leu2027Phe5 CTC 3 TTC Het None 034-020 Leu2027Phe5 CTC 3 TTC Het Pro1380Leu 034-022 Leu2027Phe5 CTC 3 TTC Het Leu541Pro 034-044 Leu2027Phe5 CTC 3 TTC Het Pro1380Leu 035-011 Leu2027Phe5 CTC 3 TTC Het None 032-063 Arg2030Gln15 CGA 3 CAA Het None 032-093 Arg2030Gln15 CGA 3 CAA Het None 2232 Briggs et al. IOVS, September 2001, Vol. 42, No. Login to comment 91 ABCA4 p.Gly863Ala ABCA4 p.Arg2139Trp ABCA4 p.Cys2150Arg ABCA4 p.Leu2035Pro ABCA4 p.Gly2146Asp ABCA4 p.Ala1637Thr ABCA4 p.Arg2107Cys ABCR Sequence Changes Found in 118 Patients with Stargardt and 8 with CRD Patient ID Mutations (Amino Acid Based) Sequence Change (Nucleotide Based) Het/Hom Other Sequence Changes 071-002 Leu2035Pro CTT 3 CCT Het None 032-064 Val2050Leu5 GTT 3 CTT Het None 032-061 Arg2107His18 CGC 3 CAC Het None 032-018 Arg2107Cys CGC 3 TGC Het Arg152Ter 032-084 Arg2139Trp CGG 3 TGG Het Thr1525Met 007-009* Gly2146Asp GGC 3 GAC Het None 032-045 Cys2150Tyr16 TGT 3 TGC Hom None 034-036 Cys2150Arg TGT 3 CGT Het Gly863Ala 034-026 Deletion Lys13-Trp15 38del9 [AGAACTGGA] Het None 034-037 Deletion Lys13-Trp15 38del9 [AGAACTGGA] Het None Polymorphisms and Rare Variants Sequence Change Alleles Among 126 Patients (n) Alleles Among Controls (n) P† 6 Nonpathogenic Missense Changes Arg212His23 CGC 3 CAC 8 10/(188) 0.3 His423Arg23 CAC 3 CGC 34 14/(178) 0.09 Arg943Gln27 CGG 3 CAG 15 9/(190) 0.7 Ala1637Thr GCC 3 ACC 1 - Not determined Asn1868Ile21 AAT 3 ATT 41 50/(170) 0.002 Pro1948Leu21 CCA 3 CTA 10 4/(190) 0.4 35 Intron and Isocoding Changes Pro47Pro CCG 3 CCA - IVS3 - 71delA - IVS3 ϩ 20C 3 T - IVS3 ϩ 26A 3 G - IVS3 ϩ 92A 3 G - IVS6 - 32T 3 C23 Thr311Thr ACC 3 ACT - IVS9 - 14C 3 T - IVS10 ϩ 6insC - IVS10 ϩ 11delG Ala626Ala GCG 3 GCA Leu988Leu CTC 3 CTT - IVS22 - 34A 3 G Pro1401Pro21 CCC 3 CCA - IVS32 - 38C 3 T23 - IVS32 - 15C 3 T - IVS33 - 16delGT23 - IVS35 - 32G 3 A - IVS38 - 50delA - IVS38 - 10T 3 C - IVS39 ϩ 6del12 [TGGTAGCCGAGG]: ins11 [CGGTCGAGGGC] - IVS40 - 25A 3 C Leu1894Leu21 CTG 3 CTC - IVS41 - 10A 3 G Leu1938Leu23 TTA 3 TTG Pro1948Pro21 CCA 3 CCG Ile2023Ile ATC 3 ATT Ile2083Ile27 ATC 3 ATT - IVS45 ϩ 7G 3 A32 Asp2095Asp21 GAT 3 GAC - IVS48 ϩ 21 C 3 T - IVS48 - 3 T 3 C - IVS49 - 85 C 3 T - IVS49 ϩ 28 G 3 C Val2244Val GTG 3 GTA References for previously reported changes are indicated in superscript in the first column (for exon sequence changes) or the second column (for intron sequence changes). Login to comment 106 ABCA4 p.Arg1640Gln The clinical findings of the three affected siblings in the family of the proband 032-030 with the R1640Q mutation have been previously reported.33 Briggs et al. IOVS, September 2001, Vol. 42, No. 10 Thirty-seven patients with Stargardt disease and one with CRD each had only one detectable sequence change that we categorized as likely to be pathogenic. Login to comment 109 ABCA4 p.Arg1640Gln The clinical findings of the three affected siblings in the family of the proband 032-030 with the R1640Q mutation have been previously reported.33 Thirty-seven patients with Stargardt disease and one with CRD each had only one detectable sequence change that we categorized as likely to be pathogenic. Login to comment 113 ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln Nucleotide 2588G 3C (Gly863Ala) and Nucleotide 2828G3A (Arg943Gln) One likely pathogenic missense change, Gly863Ala, was frequently associated with a presumed nonpathogenic missense change, Arg943Gln. Login to comment 114 ABCA4 p.Gly863Ala ABCA4 p.Arg943Gln In fact, all 9 patients who were heterozygous carriers of Gly863Ala also carried Arg943Gln. Login to comment 115 ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Arg943Gln Maugeri et al.21 also found an association between the Gly863Ala and Arg943Gln changes, but they were unable to determine whether Gly863Ala by itself was pathogenic. Login to comment 116 ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln Nucleotide 2588G 3C (Gly863Ala) and Nucleotide 2828G3A (Arg943Gln) One likely pathogenic missense change, Gly863Ala, was frequently associated with a presumed nonpathogenic missense change, Arg943Gln. Login to comment 117 ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln In fact, all 9 patients who were heterozygous carriers of Gly863Ala also carried Arg943Gln. Login to comment 118 ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Arg943Gln Maugeri et al.21 also found an association between the Gly863Ala and Arg943Gln changes, but they were unable to determine whether Gly863Ala by itself was pathogenic. Login to comment 119 ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Arg943Gln In our study, the Arg943Gln change was present in five other patients without Gly863Ala, and it was present without Gly863Ala in 9 of 190 control alleles. Login to comment 120 ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Arg943Gln In addition, a recently reported evaluation of the Gly863Ala mutant protein has shown that it has abnormal function in vitro.26 Taken together, these results indicate that Gly863Ala by itself is likely to be pathogenic and Arg943Gln by itself is not. Login to comment 121 ABCA4 p.Gly863Ala Seven of the nine patients with Stargardt disease who were carrying Gly863Ala heterozygously also carried another missense change. Login to comment 123 ABCA4 p.Gly863Ala Two patients who were heterozygous for the Gly863Ala allele had no other detectable changes likely to be pathogenic. Login to comment 142 ABCA4 p.Gly863Ala Of the eight patients carrying Gly863Ala reported by Maugeri et al.,21 five were compound heterozygotes with a null mutation affecting the other allele. Login to comment 143 ABCA4 p.Gly863Ala This led to speculation that the Gly863Ala sequence change is only pathogenic when present in TABLE 2. Login to comment 144 ABCA4 p.Arg2107His ABCA4 p.Val2050Leu ABCA4 p.Glu1122Lys ABCA4 p.Gly65Glu ABCA4 p.Ala60Val ABCA4 p.Leu2035Pro Missense Changes Found in Patients with No Other Detected ABCR Changes Patient ID Missense Change Mouse abc134 Mouse abc234 Human ABCC35 032-069 Ala60Val Ala N/A Glu 032-028 Gly65Glu Gly N/A Leu 032-044 Gly550Arg* Gly N/A N/A 032-038 Trp821Argߥ Trp N/A Trp 035-019, 032-097 Glu1122Lys Glu Glu Glu 032-063, 032-093 Arg2030Glnߤ Arg Arg Arg 071-002 Leu2035Pro Phe Leu Met 032-064 Val2050Leu Phe Val Cys 032-061 Arg2107His Arg Arg Arg 007-009 Gly2146Aspߥ Gly Gly Gly Residues at homologous locations in other ABCR proteins. Login to comment 145 ABCA4 p.Gly863Ala Of the eight patients carrying Gly863Ala reported by Maugeri et al.,21 five were compound heterozygotes with a null mutation affecting the other allele. Login to comment 146 ABCA4 p.Gly863Ala This led to speculation that the Gly863Ala sequence change is only pathogenic when present in TABLE 2. Login to comment 147 ABCA4 p.Arg2107His ABCA4 p.Val2050Leu ABCA4 p.Glu1122Lys ABCA4 p.Gly65Glu ABCA4 p.Ala60Val ABCA4 p.Leu2035Pro Missense Changes Found in Patients with No Other Detected ABCR Changes Patient ID Missense Change Mouse abc134 Mouse abc234 Human ABCC35 032-069 Ala60Val Ala N/A Glu 032-028 Gly65Glu Gly N/A Leu 032-044 Gly550Arg* Gly N/A N/A 032-038 Trp821Arg‡ Trp N/A Trp 035-019, 032-097 Glu1122Lys Glu Glu Glu 032-063, 032-093 Arg2030Gln† Arg Arg Arg 071-002 Leu2035Pro Phe Leu Met 032-064 Val2050Leu Phe Val Cys 032-061 Arg2107His Arg Arg Arg 007-009 Gly2146Asp‡ Gly Gly Gly Residues at homologous locations in other ABCR proteins. Login to comment 155 ABCA4 p.Arg1640Gln ABCA4 p.Gly2146Asp A fifth patient with CRD (032-030) was homozygous for the missense change Arg1640Gln and a sixth patient (007-009) had the missense change Gly2146Asp and no other sequence changes that we were able to detect. Login to comment 158 ABCA4 p.Arg1640Gln ABCA4 p.Gly2146Asp A fifth patient with CRD (032-030) was homozygous for the missense change Arg1640Gln and a sixth patient (007-009) had the missense change Gly2146Asp and no other sequence changes that we were able to detect. Login to comment