Submissions for variant NM_152564.5(VPS13B):c.1289G>C (p.Gly430Ala)

gnomAD frequency: 0.00006  dbSNP: rs147448147

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000379674	SCV000470765	uncertain significance	Cohen syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV002311430	SCV000846950	uncertain significance	Inborn genetic diseases	2021-09-14	criteria provided, single submitter	clinical testing	The c.1289G>C (p.G430A) alteration is located in exon 9 (coding exon 8) of the VPS13B gene. This alteration results from a G to C substitution at nucleotide position 1289, causing the glycine (G) at amino acid position 430 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000379674	SCV003018382	uncertain significance	Cohen syndrome	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 430 of the VPS13B protein (p.Gly430Ala). This variant is present in population databases (rs147448147, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 361041). 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 VPS13B protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000379674	SCV003820421	uncertain significance	Cohen syndrome	2022-08-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000379674	SCV002079463	uncertain significance	Cohen syndrome	2020-02-11	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004725187	SCV005337085	uncertain significance	VPS13B-related disorder	2024-04-10	no assertion criteria provided	clinical testing	The VPS13B c.1289G>C variant is predicted to result in the amino acid substitution p.Gly430Ala. This variant has been reported as a variant of uncertain significance in a study of individuals with clinical blindness (Diñeiro et al. 2020. PubMed ID: 32483926). This variant is reported in 0.027% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.