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

gnomAD frequency: 0.00213  dbSNP: rs35765535

Total submissions: 6

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	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000114242	SCV000316326	likely benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV001719853	SCV000581902	likely benign	not provided	2021-03-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19574260)
Illumina Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000114242	SCV002104103	likely benign	not specified	2022-02-26	criteria provided, single submitter	clinical testing	Variant summary: TMEM67 c.1309C>G (p.Leu437Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 251080 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.75 fold of the estimated maximal expected allele frequency for a pathogenic variant in TMEM67 causing Joubert Syndrome And Related Disorders phenotype (0.0018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Although reported in the literature, to our knowledge, no penetrant association of c.1309C>G in individuals affected with Joubert Syndrome And Related Disorders has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (example, Leitch_2008). These results showed no damaging effect of this variant. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign.