Submissions for variant NM_000350.3(ABCA4):c.1648G>A (p.Gly550Arg)

gnomAD frequency: 0.00001  dbSNP: rs61748558

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000085413	SCV000321338	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: 24713488, 17982420, 22229821, 28559085, 30093795, 31589614, 33732702, 22264887, 24317291, 32619608, 31968401, 11726554, 11527935, 15192030, 33090715, 29925512)
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000761253	SCV000891210	likely pathogenic	Retinitis pigmentosa 19	2017-08-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763048	SCV000893529	likely pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-04-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778263	SCV000914435	likely pathogenic	ABCA4-related disorder	2018-10-25	criteria provided, single submitter	clinical testing	The ABCA4 c.1648G>A (p.Gly550Arg) missense variant has been identified in at least seven studies in which it is found in a total of seven individuals including in three in a compound heterozygous state with a known pathogenic variant and four in a heterozygous state with an undetected second allele (Shroyer et al., 2001; Briggs et al., 2001; Stenirri et al., 2004; Thiadens et al 2012; Bertelsen et al. 2014; Fujinami et al., 2015; Salles et al. 2018). Six of these individuals exhibited Stargardt disease and the seventh exhibited generalized choriocapillaris dystrophy. The p.Gly550Arg variant was absent from 100 control chromosomes (Shroyer et al., 2001) and is reported at a frequency of 0.00006 in the South Asian population of the Exome Aggregation Consortium, but this is based on one allele, so the variant is presumed to be rare. Based on the evidence, the p.Gly550Arg variant is classified as likely pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
The Cell Therapy Center, The University of Jordan	RCV000782281	SCV000920582	pathogenic	Cone-rod dystrophy 3	2019-03-15	criteria provided, single submitter	research	This variant was classified as pathogenic based on its segregation with the disease, allele frequency, and in-silico tools. One patient with this variant was found to have sectoral RP features.
Blueprint Genetics	RCV001074836	SCV001240436	pathogenic	Retinal dystrophy	2019-07-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085413	SCV001401167	pathogenic	not provided	2024-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 550 of the ABCA4 protein (p.Gly550Arg). This variant is present in population databases (rs61748558, gnomAD 0.003%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 11726554, 28559085, 29925512). 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: 99070). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085413	SCV001446892	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000778263	SCV004113435	pathogenic	ABCA4-related disorder	2023-08-14	criteria provided, single submitter	clinical testing	The ABCA4 c.1648G>A variant is predicted to result in the amino acid substitution p.Gly550Arg. This variant has been reported many times as causative for autosomal recessive retinal dystrophy (see for examples Shroyer et al. 2001. PubMed ID: 11726554; Bertelsen et al. 2014. PubMed ID: 24713488; Table S1 in Stone. 2017. PubMed ID: 28559085; Zhu et al. 2021. PubMed ID: 33732702). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94528780-C-T). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99070/). Given the evidence, we interpret c.1648G>A (p.Gly550Arg) as pathogenic.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074836	SCV005073360	pathogenic	Retinal dystrophy	2008-01-01	criteria provided, single submitter	clinical testing
Retina International	RCV000085413	SCV000117550	not provided	not provided		no assertion provided	not provided
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV004558302	SCV005046934	pathogenic	Stargardt disease 3		no assertion criteria provided	research