Submissions for variant NM_152564.5(VPS13B):c.11009G>A (p.Arg3670Lys)

gnomAD frequency: 0.00004  dbSNP: rs370172252

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001164309	SCV001326429	uncertain significance	Cohen syndrome	2018-01-12	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.
Genetic Services Laboratory, University of Chicago	RCV001819865	SCV002066847	uncertain significance	not specified	2021-03-08	criteria provided, single submitter	clinical testing	DNA sequence analysis of the VPS13B gene demonstrated a sequence change, c.11084G>A, in exon 57 that results in an amino acid change, p.Arg3695Lys. This sequence change has been described in gnomAD with a population frequency of 0.0021% (dbSNP rs370172252). The p.Arg3695Lys change affects a moderately conserved amino acid residue located in a domain of the VPS13B protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg3695Lys substitution. This sequence change does not appear to have been previously described in patients with VPS13B-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Arg3695Lys change remains unknown at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001164309	SCV003249500	uncertain significance	Cohen syndrome	2022-08-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 3695 of the VPS13B protein (p.Arg3695Lys). This variant is present in population databases (rs370172252, gnomAD 0.008%). 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: 911705). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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.
PreventionGenetics, part of Exact Sciences	RCV003945884	SCV004760195	uncertain significance	VPS13B-related disorder	2024-09-20	no assertion criteria provided	clinical testing	The VPS13B c.11009G>A variant is predicted to result in the amino acid substitution p.Arg3670Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0080% 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.