ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.579_580del (p.Gly195fs) (rs386834202)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000194151 SCV000249164 pathogenic Joubert syndrome 6 2014-06-18 criteria provided, single submitter clinical testing
UW Hindbrain Malformation Research Program,University of Washington RCV000194151 SCV000256519 pathogenic Joubert syndrome 6 2015-02-23 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000279833 SCV000475326 likely pathogenic TMEM67-Related Disorders 2017-04-28 criteria provided, single submitter clinical testing The TMEM67 c.579_580delAG (p.Gly195IlefsTer13) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Gly195IlefsTer13 variant has been reported in five studies in which it is found in a total of seven individuals, including one homozygote and one compound heterozygote with Meckel syndrome, one homozygote with either Meckel or Joubert syndrome, two compound heterozygotes with Joubert syndrome, and two compound heterozygotes with COACH syndrome (Brancati et al. 2009; Iannicelli et al. 2010; Halbritter et al. 2013; Bachmann-Gagescu et al. 2015; Watson et al. 2016). Control data are unavailable for the p.Gly195IlefsTer13 variant, which is reported at a frequency of 0.00048 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and due to the potential impact of frameshift variants, the p.Gly195IlefsTer13 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.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000514413 SCV000610701 pathogenic not provided 2017-05-30 criteria provided, single submitter clinical testing
GeneDx RCV000514413 SCV000748408 pathogenic not provided 2018-10-13 criteria provided, single submitter clinical testing The c.579_580delAG variant in the TMEM37 gene has been reported previously in association with Joubert syndrome and related disorders when present in the homozygous state or with another variant in the TMEM37 gene (Iannicelli et al., 2010; Watson et al., 2016; Summers et al., 2017). The c.579_580delAG variant causes a frameshift starting with codon Glycine 195, changes this amino acid to an Isoleucine residue, and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Gly195IlefsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.579_580delAG variant is observed in 5/10152 (0.049%) alleles from individuals of Ashkenazi Jewish background in large population cohorts and no individuals are reported to be homozygous (Lek et al., 2016). We interpret c.579_580delAG as a pathogenic variant.
Invitae RCV000636962 SCV000758410 pathogenic Joubert syndrome; Meckel-Gruber syndrome 2020-09-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly195Ilefs*13) in the TMEM67 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs386834202, ExAC 0.05%). This variant has been reported as homozygous or in combination with another TMEM67 variant in individuals with Joubert syndrome, COACH syndrome or Meckel-Gruber syndrome (PMID: 19058225, 28431631, 26729329, 26092869, 23559409, 20232449). ClinVar contains an entry for this variant (Variation ID: 56783). Loss-of-function variants in TMEM67 are known to be pathogenic (PMID: 20232449). For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000050196 SCV000082606 probable-pathogenic Meckel syndrome, type 3 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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