Submissions for variant NM_152564.5(VPS13B):c.5244dup (p.Val1749fs)

dbSNP: rs752399634

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001048301	SCV001212296	pathogenic	Cohen syndrome	2024-11-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val1774Serfs*5) in the VPS13B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VPS13B are known to be pathogenic (PMID: 15141358, 16648375, 20461111). This variant is present in population databases (rs752399634, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with clinical features of VPS13B-related disease (PMID: 25533962). ClinVar contains an entry for this variant (Variation ID: 845268). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001547806	SCV001767598	pathogenic	not provided	2021-01-19	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25533962, 26633542)
Fulgent Genetics, Fulgent Genetics	RCV001048301	SCV002775927	pathogenic	Cohen syndrome	2022-02-14	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001048301	SCV003922263	pathogenic	Cohen syndrome	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Val1774SerfsTer5 variant in VPS13B was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 2826), in one individual with Cohen syndrome. Trio exome analysis revealed that this variant was in trans with a pathogenic variant (ClinVar Variation ID: 2826). The p.Val1774SerfsTer5 variant in VPS13B has been previously reported in 2 unrelated individuals with Cohen syndrome (PMID: 25533962, PMID: 26633542) but has been identified in 0.005% (1/19860) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs752399634). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these previously reported affected individuals (PMID: 25533962, PMID: 26633542), one was a compound heterozygote who carried a reported pathogenic variant in trans (ClinVar Variation ID: 56683), which increases the likelihood that the p.Val1774SerfsTer5 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 845268) and has been interpreted as pathogenic by GeneDx, Invitae, Fulgent Genetics, and Natera, Inc. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1774 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the VPS13B gene is an established disease mechanism in autosomal recessive Cohen syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Cohen syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Strong (Richards 2015).
Natera, Inc.	RCV001048301	SCV002082573	pathogenic	Cohen syndrome	2021-10-06	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004743262	SCV005351239	pathogenic	VPS13B-related disorder	2024-03-13	no assertion criteria provided	clinical testing	The VPS13B c.5244dupA variant is predicted to result in a frameshift and premature protein termination (p.Val1749Serfs*5). This variant was reported in the compound heterozygous state in an individual with microcephaly, agenesis of the corpus callosum, severe neonatal hypotonia, high palate, metatarsus adductus, short/broad feet, and paroxysmal dyskinesia (Fitzgerald et al. 2015. PubMed ID: 25533962, supplementary data). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. Frameshift variants in VPS13B are expected to be pathogenic. This variant is interpreted as pathogenic.