ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.1319G>A (p.Arg440Gln)

gnomAD frequency: 0.00004  dbSNP: rs386834182
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000430117 SCV000521233 pathogenic not provided 2022-06-22 criteria provided, single submitter clinical testing Published functional studies in a knockout mouse model demonstrate a damaging effect with abolished binding to Wnt5a (Abdelhamed et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17377820, 19058225, 20232449, 26729329, 26275793, 19466712, 30266093, 17397051, 26035863)
Baylor Genetics RCV000050177 SCV000807624 uncertain significance Meckel syndrome, type 3 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 variant (C78Y) in a fetus with features of Meckel-Gruber syndrome. A second affected fetus from this family was also compound heterozygous for these variants. Heterozygotes are expected to be asymptomatic carriers.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001804788 SCV002051124 pathogenic Joubert syndrome and related disorders 2021-12-14 criteria provided, single submitter clinical testing Variant summary: TMEM67 c.1319G>A (p.Arg440Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251216 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in TMEM67 causing Joubert Syndrome and Related Disorders (0.0018), allowing no conclusion about variant significance. The variant, c.1319G>A, has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Joubert Syndrome and Related Disorders (Consugar_2007, Khaddour_2007, Tallila_2009, Brancati_2009, Iannicelli_2010), including segregation evidence in some families (Consugar_2007, Tallila_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated that the variant abolished binding to Wnt5a, and failed to restore the de-regulated Wnt/beta-catenin signaling in Tmem67 -/- mouse embryonic fibroblasts (Abdelhamed_2015).Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS, likely pathogenic or pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetic Services Laboratory,University of Chicago RCV000430117 SCV002064391 likely pathogenic not provided 2018-04-02 criteria provided, single submitter clinical testing
Invitae RCV001853069 SCV002233275 pathogenic Joubert syndrome; Meckel-Gruber syndrome 2021-08-20 criteria provided, single submitter clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000050177 SCV000082587 probable-pathogenic Meckel syndrome, type 3 no assertion criteria provided not provided Converted during submission to Likely pathogenic.
PerkinElmer Genomics RCV000430117 SCV002016910 likely pathogenic not provided 2021-02-01 no assertion criteria provided clinical testing

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