Submissions for variant NM_000350.3(ABCA4):c.1957C>T (p.Arg653Cys)

gnomAD frequency: 0.00001  dbSNP: rs61749420

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074668	SCV000281839	pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085452	SCV000574771	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	ABCA4: PM3:Very Strong, PM2, PM5, PP4, PS3:Supporting
Fulgent Genetics, Fulgent Genetics	RCV000763047	SCV000893528	likely pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085452	SCV001202188	pathogenic	not provided	2024-11-27	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 653 of the ABCA4 protein (p.Arg653Cys). This variant is present in population databases (rs61749420, gnomAD 0.003%). This missense change has been observed in individual(s) with cone rod dystrophy and Stargardt disease (PMID: 23776498, 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: 99108). 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%. This variant disrupts the p.Arg653 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9466990, 10413692, 19074458). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074668	SCV001240260	pathogenic	Retinal dystrophy	2019-03-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085452	SCV001446861	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Medical Molecular Genetics, University of Zurich	RCV000408546	SCV001548139	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000085452	SCV001782833	pathogenic	not provided	2021-08-11	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33375396, 10958763, 33301772, 28559085, 23776498, 29925512, 32619608, 30204727, 23982839, 18652558, 25444351, 25097154, 23953153, 19265867, 15192030, 28355279, 27939946, 23499370, 11702214, 26957898, 26992781)
Retina International	RCV000085452	SCV000117589	not provided	not provided		no assertion provided	not provided
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000085452	SCV001957874	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000085452	SCV001968217	likely pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732662	SCV005350625	pathogenic	ABCA4-related disorder	2024-09-03	no assertion criteria provided	clinical testing	The ABCA4 c.1957C>T variant is predicted to result in the amino acid substitution p.Arg653Cys. This variant has been reported in multiple individuals with Stargardt disease or ABCA4-related retinal disease (for examples, see: Huang et al. 2013. PubMed ID: 23776498; Supplementary table 2, Fujinami K et al. 2018. PubMed ID: 29925512). Functional studies demonstrate that this variant impairs N-Ret-PE binding and stimulation of ATPase activity of the protein (Garces et al. 2020. PuMed ID 33375396). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic.