ClinVar Miner

Submissions for variant NM_017890.4(VPS13B):c.6732+1G>A (rs180177366)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000050096 SCV000807628 pathogenic Cohen syndrome 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant in a 1-year-old female with global delays, microcephaly, dysmorphic features, stereotypic movements, and MRI abnormalities; also found homozygous in a 7-year-old female with intellectual disabysability, hypotonia, dysmorphisms, short stature, microcephaly, hyperextensibility, areas of hypopigmentation, and neutropenia. Heterozygotes are expected to be asymptomatic carriers.
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000050096 SCV000803865 pathogenic Cohen syndrome 2016-08-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000050096 SCV000893771 pathogenic Cohen syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000058902 SCV000329305 pathogenic not provided 2018-06-20 criteria provided, single submitter clinical testing The 6732+1G>A variant in the VPS13B gene has been reported previously in multiple unrelated individuals with Cohen syndrome, along with another loss-of-function allele that was presumably in the compound heterozygous state (Kolehmainen et al., 2004; Seifert et al., 2006; Zhao et al., 2015). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The 6732+1G>A splice site variant destroys the canonical splice donor site in intron 37. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. We interpret 6732+1G>A as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000050096 SCV000597919 pathogenic Cohen syndrome 2015-12-30 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000050096 SCV000630881 pathogenic Cohen syndrome 2018-12-10 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 37 of the VPS13B gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs180177366, ExAC 0.003%). This variant has been reported in individuals affected with Cohen syndrome (PMID: 15141358, 16648375, 25472526). ClinVar contains an entry for this variant (Variation ID: 56683). An experimental study has shown that, in RNA isolated from an individual carrying this variant, a cryptic splice site in intron 37 was used instead of the canonical splice site. This resulted in an insertion of 4 nucleotides into the mRNA (PMID: 16648375). For these reasons, this variant has been classified as Pathogenic.
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.

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