Submissions for variant NM_152564.5(VPS13B):c.6657+1G>A

gnomAD frequency: 0.00010  dbSNP: rs180177366

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000058902	SCV000329305	pathogenic	not provided	2022-12-09	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele 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: 30144585, 25472526, 32777201, 25525159, 22527104, 19006247, 25533962, 15141358, 31980526, 21659346, 16648375)
Genetic Services Laboratory, University of Chicago	RCV000050096	SCV000597919	pathogenic	Cohen syndrome	2015-12-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000050096	SCV000630881	pathogenic	Cohen syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 37 of the VPS13B gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs180177366, gnomAD 0.009%). Disruption of this splice site has been observed in individuals with Cohen syndrome (PMID: 15141358, 16648375, 25472526). ClinVar contains an entry for this variant (Variation ID: 56683). Studies have shown that disruption of this splice site results in activation of a cryptic splice site in intron 37 and introduces a premature termination codon (PMID: 16648375). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000050096	SCV000803865	pathogenic	Cohen syndrome	2016-08-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000050096	SCV000807628	pathogenic	Cohen syndrome	2023-05-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000050096	SCV000893771	pathogenic	Cohen syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000050096	SCV000920346	pathogenic	Cohen syndrome	2017-10-13	criteria provided, single submitter	clinical testing	Variant summary: The VPS13B c.6732+1G>A variant involves the alteration of a conserved intronic nucleotide and 3/5 splice prediction tools predict an impact on normal splicing. A functional study, Seifert_2009, found the variant to affect splicing.This variant was found in 11/276880 control chromosomes at a frequency of 0.0000397, which does not exceed the estimated maximal expected allele frequency of a pathogenic VPS13B variant (0.0025). Multiple publications have cited the variant in compound heterozygote COH pts. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic/pathogenic." Taken together, this variant is classified as pathogenic.
Revvity Omics, Revvity	RCV000050096	SCV002020869	pathogenic	Cohen syndrome	2022-08-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362686	SCV002666841	pathogenic	Inborn genetic diseases	2017-10-12	criteria provided, single submitter	clinical testing	The c.6732+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 36 of the VPS13B gene. This mutation has been identified in individuals with clinical features of Cohen syndrome in conjunction with a second pathogenic VPS13B alteration (Kolehmainen J et al. Am. J. Hum. Genet., 2004 Jul;75:122-7; Seifert W et al. J. Med. Genet., 2006 May;43:e22; Zhao L et al. Hum. Genet., 2015 Feb;134:217-30). In addition, RNA studies of one patient with this alteration demonstrated defective splicing with introduction of four additional nucleotides in the transcript (Seifert W et al. J. Med. Genet., 2006 May;43:e22). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000050096	SCV002766950	pathogenic	Cohen syndrome	2022-09-02	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) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Studies have shown that disruption of this splice site results in activation of a cryptic splice site in intron 37 and introduces a premature termination codon which results a variant predicted to cause nonsense-mediated decay (NMD) and loss of protein (PMID: 16648375). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site, is present in gnomAD (v3) at a frequency of 0.00002 (1 heterozygote, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). Another canonical splice site variant, c.6657+1G>T using an alternative transcript, has also been reported as pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic in ClinVar and reported in patients with Cohen syndrome (PMID: 15141358, 16648375). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050096	SCV000082505	probable-pathogenic	Cohen syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
SNPedia	RCV000058902	SCV000090423	pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
GenomeConnect, ClinGen	RCV000050096	SCV000840256	not provided	Cohen syndrome		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Counsyl	RCV000050096	SCV001132512	likely pathogenic	Cohen syndrome	2015-10-09	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000050096	SCV001456862	pathogenic	Cohen syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407433	SCV004114876	pathogenic	VPS13B-related disorder	2024-02-09	no assertion criteria provided	clinical testing	The VPS13B c.6657+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, also referred to as c.6732+1G>A in an alternate transcript (NM_017890.4), has been reported in the compound heterozygous state in multiple patients with Cohen Syndrome (Kolehmainen et al. 2004. PubMed ID: 15141358; Seifert et al. 2006. PubMed ID: 16648375). This variant has also been found in a patient with retinitis pigmentosa (Zhao et al. 2014. PubMed ID: 25472526). Functional analysis showed that this variant leads to the addition of 4 bases within the mRNA transcript (Seifert et al. 2006. PubMed ID: 16648375). This variant has been interpreted by multiple laboratories in ClinVar as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/56683/) and has been reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Given the evidence, we interpret c.6657+1G>A as pathogenic.