ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4469G>A (p.Cys1490Tyr)

gnomAD frequency: 0.00003  dbSNP: rs61751402
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) RCV000085641 SCV000229300 pathogenic not provided 2016-03-31 criteria provided, single submitter clinical testing
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000177442 SCV000281893 pathogenic Severe early-childhood-onset retinal dystrophy 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085641 SCV000511898 pathogenic not provided 2021-05-17 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect with reduced basal and retinal ATPase activities relative to wild-type (Sun et al., 2000; Wiszniewski et al., 2005); A functional study in transgenic tadpoles demonstrated that the presence of the C1490Y variant results in impaired protein folding and localization (Wiszniewski et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24713488, 25472526, 9973280, 23695285, 25082885, 25097241, 16103129, 26261413, 11017087, 28118664, 29310964, 15161829, 16917483, 30204727, 29925512, 32467599, 31980526, 32581362)
Illumina Laboratory Services,Illumina RCV000779003 SCV000915444 pathogenic ABCA4-Related Disorders 2018-08-14 criteria provided, single submitter clinical testing Across a selection of the available literature, the ABCA4 c.4469G>A (p.Cys1490Tyr) missense variant has been identified in one individual with cone rod dystrophy in a compound heterozygous state and in eight individuals with Stargardt disease, including in one in a homozygous state, in six in a compound heterozygous state, and in one in a heterozygous state. The individual who was heterozygous for the p.Cys1490Tyr variant also carried two additional variants for which zygosity was not determined (Lewis et al. 1999; Stenirri et al. 2004; Wiszniewski et al. 2005). The p.Cys1490Tyr variant has not been seen in the literature in association with autosomal recessive retinitis pigmentosa or autosomal dominant macular degeneration. The p.Cys1490Tyr variant was absent from 220 controls and is reported at a frequency of 0.00038 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression of the p.Cys1490Tyr variant protein in HEK293 cells revealed protein levels comparable to wild type but somewhat reduced basal ATPase activity (Sun et al. 2000). Expression in COS7 cells revealed that variant protein resulted in the rate of ATP hydrolysis being decreased to 21.4% of wild type. Expression in transgenic frogs demonstrated that the p.Cys1490Tyr variant protein was mislocalized (Wiszniewski et al. 2005). Based on the collective evidence, the p.Cys1490Tyr variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000085641 SCV001223094 pathogenic not provided 2021-12-15 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1490 of the ABCA4 protein (p.Cys1490Tyr). This variant is present in population databases (rs61751402, gnomAD 0.01%). This missense change has been observed in individual(s) with Stargardt disease and retinitis pigmentosa (PMID: 23695285, 24713488, 25082885, 25472526, 28041643). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of South African ancestry (PMID: 23695285, 24713488, 25082885, 25472526, 28041643). ClinVar contains an entry for this variant (Variation ID: 99288). 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. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 16103129). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000210300 SCV001240421 pathogenic Retinal dystrophy 2019-07-16 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000085641 SCV001248242 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000085641 SCV001446683 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear RCV000177442 SCV001573455 pathogenic Severe early-childhood-onset retinal dystrophy 2021-04-08 criteria provided, single submitter research The ABCA4 c.4469G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM3-S, PS3. Based on this evidence we have classified this variant as Pathogenic.
Genomics England Pilot Project,Genomics England RCV001542643 SCV001760054 pathogenic Retinitis pigmentosa 19 criteria provided, single submitter clinical testing
Retina International RCV000085641 SCV000117780 not provided not provided no assertion provided not provided
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV000210300 SCV000259105 pathogenic Retinal dystrophy 2015-01-30 no assertion criteria provided clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000177442 SCV000598975 likely pathogenic Severe early-childhood-onset retinal dystrophy 2015-01-01 no assertion criteria provided research
GenomeConnect, ClinGen RCV000177442 SCV000607272 not provided Severe early-childhood-onset retinal dystrophy no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787763 SCV000926768 pathogenic Macular dystrophy 2018-04-01 no assertion criteria provided research
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000085641 SCV001807118 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000085641 SCV001959932 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000085641 SCV001964502 pathogenic not provided no assertion criteria provided clinical testing

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