Submissions for variant NM_000350.3(ABCA4):c.1958G>A (p.Arg653His)

gnomAD frequency: 0.00004  dbSNP: rs141823837

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484928	SCV000564521	likely pathogenic	not provided	2014-06-19	criteria provided, single submitter	clinical testing	A novel R653H variant that is likely pathogenic was identified in the ABCA4 gene. The R653H variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The R653H variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in an external database.The R653H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Another missense variant at the same residue (R653C) has been reported in the Human Gene Mutation Database in association with Stargardt disease (Stenson et al., 2009), supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Blueprint Genetics	RCV001075584	SCV001241211	pathogenic	Retinal dystrophy	2019-01-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000484928	SCV001245784	pathogenic	not provided	2017-07-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000484928	SCV001383104	pathogenic	not provided	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 653 of the ABCA4 protein (p.Arg653His). This variant is present in population databases (rs141823837, gnomAD 0.02%). This missense change has been observed in individuals with Stargardt disease (PMID: 25346251, 29975949; internal data). ClinVar contains an entry for this variant (Variation ID: 417982). 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: 23776498, 28559085). 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.
PreventionGenetics, part of Exact Sciences	RCV004529602	SCV004103881	pathogenic	ABCA4-related disorder	2023-10-10	criteria provided, single submitter	clinical testing	The ABCA4 c.1958G>A variant is predicted to result in the amino acid substitution p.Arg653His. This variant has been reported in the compound heterozygous state in individuals with Stargardt disease (Bauwens et al. 2015. PubMed ID: 25346251; Table S2 in Liu. 2020. PubMed ID: 33090715; Moon et al. 2022. PubMed ID: 35052368). A functional study using protein expression in cell culture found that the p.Arg653His substitution decreases the protein functions of substrate binding and ATPase activation (Garces et al. 2020. PubMed ID: 33375396). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94526295-C-T). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94526295-C-T). Given the evidence, we interpret this variant as pathogenic.