Submissions for variant NM_152564.5(VPS13B):c.9131A>C (p.Glu3044Ala)

gnomAD frequency: 0.00012  dbSNP: rs376652526

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179076	SCV000231268	uncertain significance	not provided	2015-03-31	criteria provided, single submitter	clinical testing
Invitae	RCV000529168	SCV000630894	uncertain significance	Cohen syndrome	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 3069 of the VPS13B protein (p.Glu3069Ala). This variant is present in population databases (rs376652526, 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: 197914). 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.
Fulgent Genetics, Fulgent Genetics	RCV000529168	SCV000897409	uncertain significance	Cohen syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000529168	SCV001322377	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201187	SCV001372251	uncertain significance	not specified	2020-06-16	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.9206A>C (p.Glu3069Ala) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251212 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in VPS13B causing Cohen Syndrome (0.00014 vs 0.0025), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.9206A>C in individuals affected with Cohen Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003416098	SCV004118146	uncertain significance	VPS13B-related disorder	2023-12-05	criteria provided, single submitter	clinical testing	The VPS13B c.9131A>C variant is predicted to result in the amino acid substitution p.Glu3044Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.029% 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.
Natera, Inc.	RCV000529168	SCV002082701	uncertain significance	Cohen syndrome	2020-02-05	no assertion criteria provided	clinical testing