ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.1309C>G (p.Leu437Val) (rs35765535)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000114242 SCV000147800 likely benign not specified 2014-02-18 criteria provided, single submitter clinical testing
Invitae RCV000200297 SCV000253658 likely benign Joubert syndrome; Meckel-Gruber syndrome 2020-11-26 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000114242 SCV000316326 likely benign not specified criteria provided, single submitter clinical testing
GeneDx RCV000114242 SCV000581902 uncertain significance not specified 2017-04-25 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TMEM67 gene. The L437V variant has been reported previously in association with Meckel syndrome; however, additional information was not provided (Doherty et al., 2010). The L437V variant is observed in 20/6586 (0.3%) alleles from individuals of European background (Lek et al., 2016). This substitution occurs at a position that is conserved in mammals. Missense variants in nearby residues (R440Q, R441C, R441L) have been reported in the Human Gene Mutation Database in association with JSRD (Stenson et al., 2014). However, the L437V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV001161604 SCV001323496 uncertain significance Meckel syndrome, type 3 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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