Submissions for variant NM_000350.3(ABCA4):c.2972G>T (p.Gly991Val)

dbSNP: rs1297410481

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001999928	SCV002234752	pathogenic	not provided	2023-07-17	criteria provided, single submitter	clinical testing	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. This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 991 of the ABCA4 protein (p.Gly991Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ABCA4-related conditions (PMID: 23982839, 32036094). ClinVar contains an entry for this variant (Variation ID: 1452669). This variant disrupts the p.Gly991 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11379881, 25066811, 28446513, 32278709). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526889	SCV005040649	uncertain significance	not specified	2024-03-27	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.2972G>T (p.Gly991Val) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes (gnomAD). c.2972G>T has been reported in the literature as a biallelic genotype in individuals affected with or with clinical features of Stargardt Disease, although the presence and/or identity of a second variant was not always specified (e.g. Fujinami_2013, Rodriguez-Munoz_2020, Glinton_2022, Cornelis_2022). These data do not allow any strong conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a missense variant affecting the same codon but resulting in a different amino acid change (p.Gly991Arg) has been classified as pathogenic and has been reported in affected individuals in the HGMD database, suggesting this residue may be important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 35120629, 23982839, 36178783, 32036094, 34996991). ClinVar contains an entry for this variant (Variation ID: 1452669). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.