Submissions for variant NM_000350.3(ABCA4):c.677G>A (p.Arg226His)

dbSNP: rs144310835

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000901876	SCV001046269	likely benign	not provided	2025-01-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001098366	SCV001254726	uncertain significance	ABCA4-related disorder	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000901876	SCV001805487	uncertain significance	not provided	2023-07-20	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000901876	SCV001959424	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000901876	SCV001975544	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001098366	SCV005350198	uncertain significance	ABCA4-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The ABCA4 c.677G>A variant is predicted to result in the amino acid substitution p.Arg226His. To our knowledge, this variant has not been reported in the literature. Variants impacting the same amino acid have been reported in individuals with inherited retinal disease (c.676C>A, p.Arg226Ser, Supplementary Table 1, Weisschuh et al. 2024. PubMed ID: 37734845 and c.677G>T, Arg226Leu, Ramkumar et al. 2017. PubMed ID: 28005406). However, in one of these reports, additional variants were detected that more likely explained the cause of disease (Weisschuh et al. 2024. PubMed ID: 37734845). The c.677G>A (p.Arg226His) variant is reported in 0.16% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.