Submissions for variant NM_152564.5(VPS13B):c.6125T>A (p.Leu2042Ter)

gnomAD frequency: 0.00001  dbSNP: rs371364257

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000278399	SCV000330508	pathogenic	not provided	2023-05-28	criteria provided, single submitter	clinical testing	Nonsense 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34840762, 35052368)
Ambry Genetics	RCV001267026	SCV001445207	pathogenic	Inborn genetic diseases	2018-11-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387318	SCV001587919	pathogenic	Cohen syndrome	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu2067*) 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 (rs371364257, gnomAD 0.006%). 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: 280580). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001387318	SCV003922264	likely pathogenic	Cohen syndrome	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Leu2067Ter variant in VPS13B was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 279780), in one individual with Cohen syndrome. Trio exome analysis revealed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 279780). The p.Leu2067Ter variant in VPS13B has not been previously reported in the literature in individuals with Cohen syndrome but has been identified in 0.005% (1/18366) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs371364257). 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. This variant has also been reported in ClinVar (Variation ID: 280580) and has been interpreted as pathogenic by Ambry, GeneDx, and Invitae. This nonsense variant leads to a premature termination codon at position 2067, which is 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Cohen syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting (Richards 2015).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001387318	SCV004847475	pathogenic	Cohen syndrome	2024-03-28	criteria provided, single submitter	clinical testing	The p.Leu2067X variant in VPS13B has been reported in the compound heterozygous state with another disease-causing variant in VPS13B in at least 2 individuals with clinical features of Cohen syndrome (Moon 2021 PMID: 35052368, ClinVar Accession: SCV003922264.1). In at least 1 individual, the VPS13B variants were confirmed to be in trans. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 280580) and has been identified in 0.005% (53/1111988) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0), consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 2067, which is predicted to lead to a truncated or absent protein. Biallelic 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, PM3, PM2_Supporting.
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV000278399	SCV004175109	pathogenic	not provided	2021-11-07	no assertion criteria provided	clinical testing