Submissions for variant NM_152564.5(VPS13B):c.10081dup (p.Thr3361fs)

gnomAD frequency: 0.00001  dbSNP: rs386834055

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000050042	SCV000220266	likely pathogenic	Cohen syndrome	2014-04-24	criteria provided, single submitter	literature only
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000050042	SCV000268521	pathogenic	Cohen syndrome	2016-03-01	criteria provided, single submitter	clinical testing	This inherited recessive pathogenic mutation in the VPS13B gene in combination with a second recessive pathogenic mutation in the same gene, NM_152564.4:c.10165_10207del, was observed in a patient with Cohen syndrome.
Invitae	RCV000050042	SCV000819826	pathogenic	Cohen syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr3386Asnfs*3) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Cohen Syndrome (PMID: 22855652). ClinVar contains an entry for this variant (Variation ID: 56629). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000050042	SCV000920341	likely pathogenic	Cohen syndrome	2019-08-12	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.10156dupA (p.Thr3386AsnfsX3) 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. The variant allele was found at a frequency of 3.6e-05 in 251338 control chromosomes. c.10156dupA has been reported in the literature in individuals affected with Cohen Syndrome (Athanasakis_2012) . These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (after 2014) and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000050042	SCV001156399	pathogenic	Cohen syndrome	2019-02-01	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000050042	SCV001737019	pathogenic	Cohen syndrome		criteria provided, single submitter	clinical testing
GeneDx	RCV001571767	SCV001796298	pathogenic	not provided	2022-03-23	criteria provided, single submitter	clinical testing	Frameshift 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: 22855652)
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000050042	SCV002600913	pathogenic	Cohen syndrome		criteria provided, single submitter	clinical testing	A homozygous single base pair duplication in exon 56 of the VPS13B gene that results in a frameshift and premature truncation of the protein 3 amino acids downstream to codon 3361 was detected. This variant has not been reported in the 1000 genomes databases. The reference region is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000050042	SCV002795133	pathogenic	Cohen syndrome	2021-11-22	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000050042	SCV002820320	pathogenic	Cohen syndrome		criteria provided, single submitter	clinical testing	The frameshift duplication p.T3386Nfs*3 in VPS13B (NM_017890.5) has previously been reported in the literature in individuals affected with Cohen Syndrome (Athanasakis_2012). The variant has been reported to ClinVar as Pathogenic/Likely Pathogenic. The p.T3386Nfs*3 variant is observed in 6/30,610 (0.0196%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The p.T3386Nfs*3 variant is a loss of function variant in the gene VPS13B, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NM_017890.5:c.292-1G>A and 155 others. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000050042	SCV003816609	likely pathogenic	Cohen syndrome	2021-11-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000050042	SCV004801540	pathogenic	Cohen syndrome	2019-02-11	criteria provided, single submitter	clinical testing	The VPS13B c.10156dupA p.(Thr3386AsnfsTer3) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in trans with a splice region variant in an Italian individual with Cohen syndrome who exhibited psychomotor development, severe language impairment, hypotonia, joint laxity, neutropenia, exotropia, macular atrophy, and friendly behavior (Athanasakis et al. 2012). The highest frequency of this allele in the Genome Aggregation Database is 0.000196 in the South Asian population (version 2.1.1). Based on the available evidence, the p.(Thr3386AsnfsTer3) variant is classified as pathogenic for Cohen syndrome.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050042	SCV000082451	probable-pathogenic	Cohen syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.