Submissions for variant NM_152564.5(VPS13B):c.5803T>G (p.Ser1935Ala)

gnomAD frequency: 0.00053  dbSNP: rs138930771

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000118842	SCV000153493	uncertain significance	not provided	2014-03-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000118842	SCV000574025	uncertain significance	not provided	2024-02-09	criteria provided, single submitter	clinical testing	Reported previously in an individual with intellectual disability, autism spectrum disorder, dysmorphic features, and abnormal brain MRI who also had a second variant in the VPS13B gene. However, the individual also harbored a variant in the EHTM1 gene, and the authors attributed the clinical phenotype to the EHTM1 variant (PMID: 28057753); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37160720, 28057753)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001246745	SCV001420127	likely benign	Cohen syndrome	2024-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354303	SCV002652799	likely benign	Inborn genetic diseases	2022-05-25	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.
Fulgent Genetics, Fulgent Genetics	RCV001246745	SCV002780637	uncertain significance	Cohen syndrome	2022-03-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155079	SCV003844804	uncertain significance	not specified	2023-02-15	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.5878T>G (p.Ser1960Ala) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251162 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in VPS13B causing Cohen Syndrome (0.00012 vs 0.0025), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.5878T>G in individuals affected with Cohen Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003915179	SCV004732188	likely benign	VPS13B-related disorder	2022-02-02	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Breakthrough Genomics, Breakthrough Genomics	RCV000118842	SCV005196058	uncertain significance	not provided		criteria provided, single submitter	not provided
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001246745	SCV001432356	likely pathogenic	Cohen syndrome		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001246745	SCV001460392	uncertain significance	Cohen syndrome	2019-10-29	no assertion criteria provided	clinical testing