Submissions for variant NM_152564.5(VPS13B):c.7708G>A (p.Asp2570Asn)

gnomAD frequency: 0.00117  dbSNP: rs140179844

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723691	SCV000113850	uncertain significance	not provided	2013-08-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000081915	SCV000491577	uncertain significance	not specified	2016-09-26	criteria provided, single submitter	clinical testing	The D2595N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project reports D2595N was observed in 16 of 4406 (0.36%) alleles from individuals of African American background, and the 1000 Genomes Project Consortium reports it was observed in 5 of 198 (2.53%) alleles in an African sub-population. The D2595N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000634120	SCV000755406	likely benign	Cohen syndrome	2025-01-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000634120	SCV000796759	uncertain significance	Cohen syndrome	2017-12-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313811	SCV000848568	likely benign	Inborn genetic diseases	2018-08-24	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.
Illumina Laboratory Services, Illumina	RCV000634120	SCV001324018	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000723691	SCV004700478	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	VPS13B: BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000081915	SCV005395047	likely benign	not specified	2024-09-10	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.7783G>A (p.Asp2595Asn) 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 0.00039 in 250724 control chromosomes, predominantly at a frequency of 0.005 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in VPS13B causing Cohen Syndrome phenotype (0.0025). To our knowledge, no experimental evidence demonstrating its impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 95868). Based on the evidence outlined above, the variant was classified as likely benign.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000634120	SCV001133239	likely pathogenic	Cohen syndrome	2019-09-26	flagged submission	clinical testing
Natera, Inc.	RCV000634120	SCV001461436	benign	Cohen syndrome	2020-06-07	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003974983	SCV004790838	likely benign	VPS13B-related disorder	2020-02-25	no assertion criteria provided	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).