Submissions for variant NM_152564.5(VPS13B):c.9185dup (p.Leu3062fs)

dbSNP: rs180177329

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000002960	SCV001227881	pathogenic	Cohen syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu3087Phefs*20) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 15211651). It has also been observed to segregate with disease in related individuals. This variant is also known as c.9258_9259insT. ClinVar contains an entry for this variant (Variation ID: 2826). 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.
Ambry Genetics	RCV001266139	SCV001444311	pathogenic	Inborn genetic diseases	2020-01-15	criteria provided, single submitter	clinical testing	The c.9260dupT (p.L3087Ffs*20) alteration, located in exon 51 (coding exon 50) of the VPS13B gene, results from a duplication of one nucleotide at position 9260, causing a translational frameshift with a predicted alternate stop codon after 20 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported in 8 affected children from an Amish kindred who were homozygous for this alteration (referred to as c.9258_9259dupT); their phenotypes included childhood-onset pigmentary retinopathy, progressive high myopia, global developmental delay, short stature, microcephaly, truncal hypotonia, joint hyperextensibility, small/narrow hands and feet, and dysmorphic facial features (Falk, 2004). Based on the available evidence, this alteration is classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000002960	SCV003922266	pathogenic	Cohen syndrome	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Leu3087PhefsTer20 variant in VPS13B was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 845268), in one individual with Cohen syndrome. Trio exome analysis revealed that this variant was in trans with a pathogenic variant (ClinVar Variation ID: 845268). The p.Leu3087PhefsTer20 variant in VPS13B has been previously reported in 2 unrelated individuals with Cohen syndrome and segregated with disease in 8 affected relatives from 2 families (PMID: 15211651). These previously reported individuals were homozygotes (PMID: 15211651), which increases the likelihood that the p.Leu3087PhefsTer20 variant is pathogenic. This variant was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 2826) and has been interpreted as pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 3087 and leads to a premature termination codon 20 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, PP1_Strong (Richards 2015).
OMIM	RCV000002960	SCV000023118	pathogenic	Cohen syndrome	2004-07-01	no assertion criteria provided	literature only
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000002960	SCV000082521	probable-pathogenic	Cohen syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
SNPedia	RCV000058940	SCV000090461	not provided	not provided		no assertion provided	not provided
GeneReviews	RCV000002960	SCV000297977	not provided	Cohen syndrome		no assertion provided	literature only
Natera, Inc.	RCV000002960	SCV001460988	pathogenic	Cohen syndrome	2020-09-16	no assertion criteria provided	clinical testing