Submissions for variant NM_152564.5(VPS13B):c.6727G>T (p.Glu2243Ter)

gnomAD frequency: 0.00006  dbSNP: rs146960401

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000398282	SCV000329306	pathogenic	not provided	2022-05-26	criteria provided, single submitter	clinical testing	Observed as heterozygous in a cohort of individuals undergoing whole genome sequencing with deep phenotyping, but clinical information was not included (Hou et al., 2020); 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; This variant is associated with the following publications: (PMID: 27535533, 31980526)
Baylor Genetics	RCV000679864	SCV000807230	pathogenic	Cohen syndrome	2017-09-01	criteria provided, single submitter	clinical testing	This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory In trans with a missense variant (L2642P) in a 5-year-old female with global delays, autistic features, short stature, microcephaly, dysmorphic features, hypotonia, joint laxity, scoliosis.
Fulgent Genetics, Fulgent Genetics	RCV000679864	SCV000893772	pathogenic	Cohen syndrome	2022-03-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000679864	SCV001214921	pathogenic	Cohen syndrome	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu2268*) 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 (rs146960401, gnomAD 0.03%). 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: 279780). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000679864	SCV002020873	pathogenic	Cohen syndrome	2020-11-12	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000398282	SCV002051678	likely pathogenic	not provided	2021-01-12	criteria provided, single submitter	clinical testing	PVS1, PM2
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000679864	SCV003922265	likely pathogenic	Cohen syndrome	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Glu2268Ter variant in VPS13B was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 280580), in one individual with Cohen syndrome. Trio exome analysis revealed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 280580). The p.Glu2268Ter variant in VPS13B has been previously reported in one individual with Cohen syndrome (PMID: 25326635) but has been identified in 0.03% (3/10360) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs146960401). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 279780) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 2268, 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, PM3 (Richards 2015).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000679864	SCV005087216	pathogenic	Cohen syndrome	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Cohen syndrome (MIM#216550). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (16 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic or pathogenic by multiple clinical laboratories in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Counsyl	RCV000679864	SCV001132314	likely pathogenic	Cohen syndrome	2014-01-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409391	SCV004108923	pathogenic	VPS13B-related disorder	2024-06-03	no assertion criteria provided	clinical testing	The VPS13B c.6727G>T variant is predicted to result in premature protein termination (p.Glu2243*). This variant is also known as c.6802G>T, (p.Glu2268*) in an alternate transcript (NM_017890.4). This variant has been documented in a prospective cohort of individuals undergoing whole-genome sequencing, comprehensive metabolomics, and advanced imaging (Supplementary Dataset 1 in Hou. 2020. PubMed ID: 31980526). This variant is reported in 0.029% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Nonsense variants in VPS13B are expected to be pathogenic. Based on this evidence, we interpret this variant as pathogenic.