Submissions for variant NM_000350.3(ABCA4):c.3385C>T (p.Arg1129Cys)

gnomAD frequency: 0.00002  dbSNP: rs779426136

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000385765	SCV000359403	likely pathogenic	ABCA4-related disorder	2023-07-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000413704	SCV000490377	pathogenic	not provided	2016-03-25	criteria provided, single submitter	clinical testing	The R1129C variant has been reported previously is association with Stargardt disease (Allikmets et al., 1997; Lewis et al., 1999). In vitro functional studies demonstrated that the presence of the R1129C variant results in decreased expressed ABCA4 protein levels in comparison to wild-type ABCA4 (Sabirzhanova et al., 2015). The R1129C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1129C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other 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. Therefore, this variant is pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413704	SCV001384454	pathogenic	not provided	2025-01-28	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 1129 of the ABCA4 protein (p.Arg1129Cys). This variant is present in population databases (rs779426136, gnomAD 0.003%). This missense change has been observed in individuals with Stargardt disease or cone dystrophy (PMID: 19074458, 25097241, 25312043, 29925512). ClinVar contains an entry for this variant (Variation ID: 298251). 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: 26092729). This variant disrupts the p.Arg1129 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19074458, 23755871, 27032803, 29114839). 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.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816524	SCV005072470	pathogenic	Retinal dystrophy	2018-01-01	criteria provided, single submitter	clinical testing
SingHealth Duke-NUS Institute of Precision Medicine	RCV005235252	SCV005881630	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2025-02-05	criteria provided, single submitter	clinical testing	Variant is located in a mutational hotspot where >50% of variants are pathogenic (PM1). Homozygous allele count in gnomAD exomes and genomes is 0 (PM2). Other variants at this amino acid residue have been classified as pathogenic (PM5, p.Arg1129Gly; p.Arg1129His). REVEL score is 0.868 (PP3_mod)