ClinVar Miner

Submissions for variant NM_153704.5(TMEM67):c.1046T>C (p.Leu349Ser) (rs386834180)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000515409 SCV000611243 likely pathogenic Bardet-Biedl syndrome; COACH syndrome; Joubert syndrome 6; Meckel syndrome type 3; Bardet-Biedl syndrome 14; Nephronophthisis 11 2017-05-18 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000114240 SCV000147797 likely pathogenic Meckel-Gruber syndrome 2013-09-13 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778866 SCV000915263 pathogenic TMEM67-Related Disorders 2017-10-12 criteria provided, single submitter clinical testing Across a selection of the available literature, the TMEM67 c.1046T>C (p.Leu349Ser) missense variant has been reported in at least seven individuals from six families with Joubert syndrome or Meckel syndrome (Khaddour et al. 2007; Iannicelli et al. 2010; Chaki et al. 2011; Bachmann-Gagescu et al. 2015). Four of the cases were terminated fetuses that met the diagnostic criteria for Meckel syndrome. In three of these cases, including one sibling pair, the variant was observed in a compound heterozygous state with a truncating variant; in the fourth case, it was found in a homozygous state. In the remaining three cases, it was observed in a compound heterozygous state with a second missense variant in individuals with Joubert syndrome. Parental inheritance of the variant was demonstrated in two of the compound heterozygous cases. The p.Leu349Ser variant was absent from at least 410 control chromosomes and is reported at a frequency of 0.000060 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies conducted in embryonic fibroblasts from Tmem67 knockout mice showed that unlike the wildtype protein, p.Leu349Ser TMEM67 was unable to rescue the impaired canonical Wnt/β-catenin signalling or deficient response to Wnt5a observed in the Tmem67-deficient cells (Abdelhamed et al. 2015). Based on the collective evidence, the p.Leu349Ser variant is classified as pathogenic for TMEM67-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000560903 SCV000634629 pathogenic Joubert syndrome; Meckel-Gruber syndrome 2017-11-15 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 349 of the TMEM67 protein (p.Leu349Ser). The leucine residue is moderately conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs386834180, ExAC 0.006%). This variant has been reported in several individuals affected with TMEM67-related ciliopathies (PMID: 17397051, 19574260, 21068128, 26729329, 20232449). ClinVar contains an entry for this variant (Variation ID: 56762). An experimental study has shown that the TMEM67 protein with this missense change cannot restore normal Wnt signaling in cells lacking endogenous TMEM67 (PMID: 26035863). For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000050175 SCV000082585 probable-pathogenic Meckel syndrome type 3 no assertion criteria provided not provided Converted during submission to Likely pathogenic.
UW Hindbrain Malformation Research Program,University of Washington RCV000201777 SCV000256491 pathogenic Joubert syndrome 6 2015-02-23 criteria provided, single submitter research

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