ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.1531C>T (p.Arg511Cys) (rs752786160)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000429156 SCV000511883 likely pathogenic not provided 2016-10-03 criteria provided, single submitter clinical testing The R511C missense variant has been reported in association with ABCA4-associated disorders (Zernant et al., 2011; Huang et al., 2015; Jiang et al., 2016). The R511C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R511C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, this variant is a likely pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000779006 SCV000915447 likely pathogenic ABCA4-Related Disorders 2017-04-28 criteria provided, single submitter clinical testing The ABCA4 c.1531C>T (p.Arg511Cys) missense variant has been reported in four studies in which it is found in a total of six individuals with an ABCA4-related disorder. One individual with an ABCA4-related disorder of an unspecified type carried the p.Arg511Cys variant in a homozygous state (Zernant et al. 2011). Two individuals with Stargardt disease and one patient with inherited retinal dystrophy carried the p.Arg511Cys variant in a compound heterozygous state with a second variant (Jiang et al. 2016; Huang et al. 2015). One individual with Stargardt disease carried the p.Arg511Cys variant along with both a duplication and a missense variant of unclear zygosity in the ABCA4 gene (Fujinami et al. 2015). One individual with cone rod dystrophy carried the p.Arg511Cys variant with a second ABCA4 variant of unknown pathogenicity in cis and a third variant in trans (Jiang et al. 2016). The p.Arg511Cys variant was absent from 464 controls and is reported at a frequency of 0.00243 in the East Asian population of the Exome Aggregate Consortium. Based on the collective evidence, the p.Arg511Cys variant is classified as likely pathogenic for autosomal recessive ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000429156 SCV001201594 likely pathogenic not provided 2019-11-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 511 of the ABCA4 protein (p.Arg511Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs752786160, ExAC 0.2%). This variant has been observed in individual(s) with ABCA4-related disease (PMID: 30060493, 25356976, 26780318, 25312043). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 377402). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Blueprint Genetics RCV001074731 SCV001240324 pathogenic Retinal dystrophy 2019-05-07 criteria provided, single submitter clinical testing

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