ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.1046T>C (p.Leu349Ser)

gnomAD frequency: 0.00004  dbSNP: rs386834180
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000114240 SCV000147797 likely pathogenic Meckel-Gruber syndrome 2013-09-13 criteria provided, single submitter clinical testing
UW Hindbrain Malformation Research Program, University of Washington RCV000201777 SCV000256491 pathogenic Joubert syndrome 6 2015-02-23 criteria provided, single submitter research
Fulgent Genetics, Fulgent Genetics RCV002477175 SCV000611243 likely pathogenic COACH syndrome 1; Joubert syndrome 6; Meckel syndrome, type 3; RHYNS syndrome; Bardet-Biedl syndrome 14; Nephronophthisis 11 2021-08-23 criteria provided, single submitter clinical testing
Invitae RCV000560903 SCV000634629 pathogenic Familial aplasia of the vermis; Meckel-Gruber syndrome 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 349 of the TMEM67 protein (p.Leu349Ser). This variant is present in population databases (rs386834180, gnomAD 0.005%). This missense change has been observed in individual(s) with TMEM67-related ciliopathies (PMID: 17397051, 19574260, 20232449, 21068128, 26729329). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56762). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMEM67 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TMEM67 function (PMID: 26035863). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina RCV000778866 SCV000915263 pathogenic TMEM67-related disorder 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001267954 SCV001446479 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
GeneDx RCV001267954 SCV002504097 pathogenic not provided 2022-04-10 criteria provided, single submitter clinical testing Published functional studies demonstrate that the L349S variant impacts protein function (Abdelhamed et al., 2015; Not observed at 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: 21068128, 19574260, 28844315, 17397051, 21866095, 19466712, 20232449, 23559409, 26092869, 26729329, 31589614, 34731008, 32160518, 26035863)
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.
Sydney Genome Diagnostics, Children's Hospital Westmead RCV000050175 SCV001449455 pathogenic Meckel syndrome, type 3 2018-09-05 no assertion criteria provided clinical testing This fetus is heterozygous for a known pathogenic variant, c.1046T>C (p.Leu349Ser), in the TMEM67 gene. This variant (dbSNP: rs386834180) has been previously reported in fetuses with Meckel syndrome in the literature (Iannicelli et al 2010 Hum Mutat 31:E1319-1331; Khaddour et al 2007 Hum Mutat 28:523-524). Functional studies have shown that this variant is pathogenic (Abdelhamed et al 2015 Disease models & Mechanisms 8:527-541)

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