ClinVar Miner

Submissions for variant NM_017890.4(VPS13B):c.5681C>T (p.Thr1894Met) (rs117148013)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000711299 SCV000229738 uncertain significance not provided 2015-03-11 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000194012 SCV000249412 uncertain significance not specified 2015-04-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515167 SCV000611530 uncertain significance Cohen syndrome 2017-05-23 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000515167 SCV000743190 benign Cohen syndrome 2014-10-09 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000515167 SCV000744233 likely benign Cohen syndrome 2015-09-21 criteria provided, single submitter clinical testing
Invitae RCV000515167 SCV000755396 uncertain significance Cohen syndrome 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1894 of the VPS13B protein (p.Thr1894Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs117148013, ExAC 0.1%). This variant has not been reported in the literature in individuals with VPS13B-related disease. ClinVar contains an entry for this variant (Variation ID: 196918). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics Inc RCV000711299 SCV000841639 uncertain significance not provided 2018-05-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV000718312 SCV000849174 likely benign History of neurodevelopmental disorder 2017-04-14 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Other data supporting benign classification
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000515167 SCV001190482 uncertain significance Cohen syndrome 2019-09-03 criteria provided, single submitter clinical testing VPS13B NM_017890.4 exon 37 p.Thr1894Met (c.5681C>T): This variant has not been reported in the literature but is present in 0.1% (50/30616) of South Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/8-100654424-C-T). This variant is also present in ClinVar (Variation ID:196918). This variant amino acid Methionine (Met) is present in several species including multiple mammals, and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Clinical Services Laboratory,Illumina RCV000515167 SCV001323925 uncertain significance Cohen syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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