Submissions for variant NM_000350.3(ABCA4):c.2461T>A (p.Trp821Arg)

gnomAD frequency: 0.00001  dbSNP: rs61749433

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001075705	SCV001241333	pathogenic	Retinal dystrophy	2019-04-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085480	SCV001380148	pathogenic	not provided	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 821 of the ABCA4 protein (p.Trp821Arg). This variant is present in population databases (rs61749433, gnomAD 0.002%). This missense change has been observed in individual(s) with Stargardt disease or cone-rod dystrophy (PMID: 9973280, 22247458, 26593885; internal data). 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: 99136). 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%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000085480	SCV002504015	pathogenic	not provided	2021-11-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 11702214, 9973280, 11328725, 18652558, 24677105, 11527935, 25301883, 19265867, 11726554, 28430335, 29925512, 33375396, 26593885, 28365912, 25283059, 25474345, 29178665, 20128570, 22247458)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586548	SCV005075864	pathogenic	Retinitis pigmentosa	2024-04-02	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.2461T>A (p.Trp821Arg) results in a non-conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of 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 8e-06 in 251166 control chromosomes. c.2461T>A has been reported in the literature in multiple individuals affected with Stargardt disease (example, Cideciyan_2012, Duncker_2015, Fumagalli_2001, Verdina_2018, Zaneveld_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22247458, 25283059, 11702214, 28365912, 25474345). ClinVar contains an entry for this variant (Variation ID: 99136). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005025148	SCV005659555	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-04-03	criteria provided, single submitter	clinical testing
Retina International	RCV000085480	SCV000117617	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV004732665	SCV005360602	pathogenic	ABCA4-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The ABCA4 c.2461T>A variant is predicted to result in the amino acid substitution p.Trp821Arg. This variant has been reported to be causative for Stargardt disease (STGD) and ABCA4-related retinopathy (Shroyer et al. 1999. PubMed ID: 10396622; Lewis et al. 1999. PubMed ID: 9973280; Shroyer et al. 2001. PubMed ID: 11726554; Webster et al. 2001. PubMed ID: 11328725; Bianco et al 2023. PubMed ID: 37498587). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99136). Given the evidence, we too interpret c.2461T>A (p.Trp821Arg) as pathogenic.