Submissions for variant NM_152564.5(VPS13B):c.5845C>T (p.Arg1949Ter)

gnomAD frequency: 0.00002  dbSNP: rs180177365

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000058901	SCV000616274	pathogenic	not provided	2016-05-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000058901	SCV000709904	pathogenic	not provided	2020-03-30	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 a significant frequency in large population cohorts (Lek et al., 2016); Identified in patients with Cohen syndrome referred for genetic testing at GeneDx and in published literature (Seifert et al., 2006); This variant is associated with the following publications: (PMID: 25525159, 16648375)
Invitae	RCV000984235	SCV001578917	pathogenic	Cohen syndrome	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1974*) 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 (rs180177365, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 16648375, 19006247). ClinVar contains an entry for this variant (Variation ID: 68089). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000984235	SCV002600718	likely pathogenic	Cohen syndrome	2022-10-25	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.5920C>T (p.Arg1974X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 250916 control chromosomes (gnomAD). c.5920C>T has been reported in the literature in at least one compound heterozygous individual affected with Cohen Syndrome (Seifert_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: four classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
SNPedia	RCV000058901	SCV000090422	pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Counsyl	RCV000984235	SCV001132315	likely pathogenic	Cohen syndrome	2014-02-18	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000984235	SCV001456859	pathogenic	Cohen syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000058901	SCV001553101	pathogenic	not provided		no assertion criteria provided	clinical testing	The VPS13B p.R1974* variant was identified in 1 of 48 proband chromosomes (frequency: 0.021) from individuals with Cohen syndrome (Seifert_2006_PMID:16648375). The variant was identified in dbSNP (ID: rs180177365) and ClinVar (classified as pathogenic by Athena Diagnostics Inc, GeneDx and SNPedia). The variant was identified in control databases in 4 of 250916 chromosomes at a frequency of 0.00001594 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 2 of 34476 chromosomes (freq: 0.000058) and European (non-Finnish) in 2 of 113478 chromosomes (freq: 0.000018), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The c.5920C>T variant leads to a premature stop codon at position 1974 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the VPS13B gene are an established mechanism of disease in Cohen syndrome and is the type of variant expected to cause the disorder when found in the homozygous or compound heterozygous state. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this has not been confirmed by RNA analysis. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.