Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
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, |
RCV000378419 | SCV000359489 | uncertain significance | Retinitis Pigmentosa, Recessive | 2016-06-14 | criteria provided, single submitter | clinical testing | |
Illumina Laboratory Services, |
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, |
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. |