ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.1522C>T (p.Arg508Cys)

gnomAD frequency: 0.00011  dbSNP: rs138157885
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000321513 SCV000359488 uncertain significance ABCA4-Related Disorders 2017-04-28 criteria provided, single submitter clinical testing The ABCA4 c.1522C>T (p.Arg508Cys) missense variant has been reported in two studies in which it is found in a total of three individuals. The variant was found in a compound heterozygous state in one individual with Stargardt disease and another with cone-rod dystrophy and in a state of unknown zygosity in one individual with macular dystrophy (Michaelides et al. 2007; Jiang et al. 2016). The p.Arg508Cys variant was absent from 100 controls and is reported at a frequency of 0.00047 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Arg508Cys variant is classified as a variant of unknown significance but suspicious for pathogenicity for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina RCV000378419 SCV000359489 uncertain significance Retinitis Pigmentosa, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000286324 SCV000359490 uncertain significance Macular degeneration 2016-06-14 criteria provided, single submitter clinical testing The c.1522C>T (p.Arg508Cys) variant has been reported in two studies and is found in a total of three patients with various phenotypes including one in a compound heterozygous state with Stargardt disease, one in a compound heterozygous state with cone-rod dystrophy and one with macular dystrophy without clear zygosity information (Michaelides et al. 2007; Jiang et al. 2016). The p.Arg508Cys variant was absent from 100 controls and is reported at a frequency of 0.00047 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Arg508Cys variant is classified as a variant of unknown significance but suspicious for pathogenicity for ABCA4-related disorders.
Blueprint Genetics RCV001073691 SCV001239250 likely pathogenic Retinal dystrophy 2017-02-13 criteria provided, single submitter clinical testing
Invitae RCV001303441 SCV001492687 pathogenic not provided 2023-12-31 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 508 of the ABCA4 protein (p.Arg508Cys). This variant is present in population databases (rs138157885, gnomAD 0.03%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 26780318, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 298258). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
DBGen Ocular Genomics RCV001590914 SCV001815949 uncertain significance Severe early-childhood-onset retinal dystrophy 2021-05-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323503 SCV004028622 pathogenic Retinitis pigmentosa 2023-07-31 criteria provided, single submitter clinical testing Variant summary: ABCA4 c.1522C>T (p.Arg508Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251082 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Retinitis Pigmentosa (0.00018 vs 0.0014), allowing no conclusion about variant significance. c.1522C>T has been reported in the literature in multiple individuals affected with macular dystrophy (Michaelides_2007), autosomal recessive stargardt Disease (examples: Jiang_2015, Stone_2017, Hu_ABCA4_2019), cone-rod dystrophy (Jiang_2015, Falsini_2022), autosomal recessive retinitis pigmentosa (examples: Ma_2021, Neveling_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35260635, 31543898, 26780318, 33691693, 18024811, 22334370, 28559085). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic for autosomal recessive stargardt disease and retinitis pigmentosa.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.