ClinVar Miner

Submissions for variant NM_001173990.3(TMEM216):c.253C>T (p.Arg85Ter) (rs11230683)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UW Hindbrain Malformation Research Program,University of Washington RCV000201650 SCV000256484 pathogenic Joubert syndrome 2 2015-02-23 criteria provided, single submitter research
Counsyl RCV000576663 SCV000678164 likely pathogenic Joubert syndrome 2; Meckel syndrome type 2 2014-01-02 criteria provided, single submitter clinical testing
GeneDx RCV000760437 SCV000890320 likely pathogenic not provided 2018-06-29 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the TMEM216 gene. The R85X variant has been reported previously as a homozygous mutation in two male infants from a British family with Meckel syndrome (Valente et al., 2010; Szymanska et al., 2012). Additionally, R85X has been identified in the heterozygous state in an individual with Joubert syndrome who also harbored a second TMEM216 variant (R73L); however, it is unknown whether these two variants were present in cis or trans (Bachmann-Gagescu et al., 2015; Summers et al., 2017). The R85X variant is observed in 7/34420 (0.02%) alleles from individuals of Latino background and in 24/276782 (0.009%) alleles globally in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Fulgent Genetics,Fulgent Genetics RCV000576663 SCV000893897 pathogenic Joubert syndrome 2; Meckel syndrome type 2 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779067 SCV000915534 pathogenic TMEM216-Related Disorders 2018-10-11 criteria provided, single submitter clinical testing The TMEM216 c.253C>T (p.Arg85Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg85Ter variant has been reported in at least two studies in which it is found in at least three individuals, including two siblings with Meckel syndrome who carried the variant in a homozygous state and one individual with Joubert syndrome who carried the variant in a compound heterozygous state (Valente et al. 2010; Bachmann-Gogescu et al. 2015). The p.Arg85Ter variant was absent from 500 controls, but is reported at a frequency of 0.00003 in the total population from the Exome Aggregation Consortium. In fibroblasts that were homozygous for the p.Arg85Ter variant, there was failure of ciliogenesis after 48h compared to controls (Valente et al. 2010). Further, this variant protein was not observed at the base of cilia in kidney cells, whereas wild type protein was observed at this location. Based on the evidence and the potential impact of stop-gained variants, the p.Arg85Ter variant is classified as pathogenic for TMEM216-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000201650 SCV000920296 pathogenic Joubert syndrome 2 2018-06-05 criteria provided, single submitter clinical testing Variant summary: TMEM216 c.253C>T (p.Arg85X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.7e-05 in 276782 control chromosomes. This frequency is not higher than expected for a pathogenic variant in TMEM216 causing Joubert Syndrome 2 (8.7e-05 vs 0.0039), allowing no conclusion about variant significance. c.253C>T has been reported in the literature in individuals affected with Meckel syndrome 2 or Joubert Syndrome 2 (Valente 2010, Summers 2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating the loss of protein expression and a failure in ciliogenesis and centrosome docking (Valente 2010). The most pronounced variant effect results in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000822982 SCV000963814 pathogenic Joubert syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg85*) in the TMEM216 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs11230683, ExAC 0.01%). This variant has been observed in individuals affected with Meckel syndrome  (PMID: 20512146, 23351400) and Joubert syndrome (PMID: 26092869, 28497568). ClinVar contains an entry for this variant (Variation ID: 56384). Experimental studies have shown that this nonsense change results in failure of ciliogenesis (PMID: 20512146). Loss-of-function variants in TMEM216 are known to be pathogenic (PMID: 20512146). For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049797 SCV000082205 probable-pathogenic Meckel syndrome type 2 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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