Submissions for variant NM_152564.5(VPS13B):c.7366G>A (p.Val2456Ile)

gnomAD frequency: 0.00027  dbSNP: rs201963516

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081912	SCV000113847	uncertain significance	not provided	2013-08-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000169023	SCV000220170	likely benign	Cohen syndrome	2014-03-14	criteria provided, single submitter	literature only
Illumina Laboratory Services, Illumina	RCV000169023	SCV000470823	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169023	SCV000821255	likely benign	Cohen syndrome	2024-11-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000169023	SCV001137685	benign	Cohen syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222383	SCV002500561	uncertain significance	not specified	2022-03-02	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.7441G>A (p.Val2481Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251362 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in VPS13B causing Cohen Syndrome (0.00017 vs 0.0025), allowing no conclusion about variant significance. c.7441G>A has been reported in the literature as a homozygous genotype in an individual who underwent diagnostic exome sequencing for severe intellectual disability (example, de Ligt_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Cohen Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002381403	SCV002671681	likely benign	Inborn genetic diseases	2017-06-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000081912	SCV005201581	uncertain significance	not provided	2024-02-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23033978, 35690661)
Fulgent Genetics, Fulgent Genetics	RCV000169023	SCV005667393	uncertain significance	Cohen syndrome	2024-05-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398677	SCV004119311	uncertain significance	VPS13B-related disorder	2024-07-02	no assertion criteria provided	clinical testing	The VPS13B c.7366G>A variant is predicted to result in the amino acid substitution p.Val2456Ile. This variant, which is referred to as c.7441G>A (p.Val2481Ile) on an alternative transcript (NM_017890), has been reported in the homozygous state in an individual with severe intellectual disability (Table S9, de Ligt et al. 2012. PubMed ID: 23033978). However, several other homozygous variants in other genes were identified in this individual and it is not clear if this variant was contributing to the phenotypes. This variant is reported in 0.036% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.