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

gnomAD frequency: 0.00006  dbSNP: rs61751402

Total submissions: 22

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	2022-09-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with reduced basal and retinal ATPase activities relative to wild-type as well as impaired protein folding and localization (Sun et al., 2000; 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, 31429209, 32531858, 33706644, 34758253, 35456422, 23695285, 25082885, 25097241, 26261413, 16103129, 28118664, 29310964, 15161829, 16917483, 30204727, 29925512, 32467599, 31980526, 32581362, 31589614, 32619608, 11017087)
Illumina Laboratory Services, Illumina	RCV000779003	SCV000915444	pathogenic	ABCA4-related disorder	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085641	SCV001223094	pathogenic	not provided	2024-12-12	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 16103129). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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
Institute of Human Genetics, University Hospital Muenster	RCV004584347	SCV002578079	pathogenic	See cases	2021-12-16	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PS4,PM3,PP1,PP4,PP5
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000210300	SCV005073405	pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000177442	SCV005399022	pathogenic	Severe early-childhood-onset retinal dystrophy	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease 1 (MIM#248200) and other inherited retinal diseases (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31522899). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. There is some evidence that this variant may affect splicing through the creation of a cryptic splice site (PMID: 37555651). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (250 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4: 1 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located at an annotated cysteine residue that is involved in a disulphide bond (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed in multiple individuals with Stargardt disease and is considered to be a founder variant in the South African population (PMID: 32913387). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005025159	SCV005658900	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-05-21	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.
Department of Clinical Genetics, Copenhagen University Hospital, 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