Submissions for variant NM_000350.3(ABCA4):c.5531G>A (p.Gly1844Asp)

dbSNP: rs1659540498

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001756526	SCV001985365	uncertain significance	not provided	2019-12-11	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23755871)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001756526	SCV002288397	pathogenic	not provided	2023-09-06	criteria provided, single submitter	clinical testing	This variant disrupts the p.Gly1844 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 1303027). This missense change has been observed in individual(s) with Stargardt disease (PMID: 23755871). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1844 of the ABCA4 protein (p.Gly1844Asp).
PreventionGenetics, part of Exact Sciences	RCV004536279	SCV004103662	uncertain significance	ABCA4-related disorder	2023-09-08	criteria provided, single submitter	clinical testing	The ABCA4 c.5531G>A variant is predicted to result in the amino acid substitution p.Gly1844Asp. This variant has been reported along with a second ABCA4 variant in an individual with Stargardt disease (Riveiro-Alvarez et al. 2013. PubMed ID: 23755871). At PreventionGenetics, this variant has been observed along with a pathogenic variant in an individual undergoing testing for Stargardt disease (internal data). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.