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

dbSNP: rs11230683

Total submissions: 12

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	RCV001787335	SCV000678164	likely pathogenic	Joubert syndrome 2; Meckel syndrome, type 2	2014-01-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000760437	SCV000890320	pathogenic	not provided	2023-01-27	criteria provided, single submitter	clinical testing	Observed in homozygous state in two siblings with Meckel syndrome in published literature (Valente et al., 2010; Szymanska et al., 2012) and in a fetus with encephalocele, kidney anomaly, eye abnormality, microcephaly, club foot, and short limbs previously tested at GeneDx, and not observed in homozygous state in controls; Observed in the heterozygous state with another variant in the TMEM216 gene in a patient with Joubert syndrome in published literature; however, it is unknown whether the two variants were present in cis or trans (Bachmann-Gagescu et al., 2015; Summers et al., 2017); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20512146, 21068128, 23351400, 26092869, 28497568, 31589614)
Fulgent Genetics, Fulgent Genetics	RCV001787335	SCV000893897	pathogenic	Joubert syndrome 2; Meckel syndrome, type 2	2022-02-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	Familial aplasia of the vermis	2024-01-27	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. Loss-of-function variants in TMEM216 are known to be pathogenic (PMID: 20512146). This variant is present in population databases (rs11230683, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Meckel syndrome or Joubert syndrome (PMID: 20512146, 23351400, 26092869, 28497568). ClinVar contains an entry for this variant (Variation ID: 56384). For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000760437	SCV002064402	pathogenic	not provided	2017-07-24	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000760437	SCV002525803	pathogenic	not provided	2023-06-13	criteria provided, single submitter	clinical testing	PM2, PS3, PVS1
PreventionGenetics, part of Exact Sciences	RCV003398640	SCV004120095	pathogenic	TMEM216-related condition	2023-06-27	criteria provided, single submitter	clinical testing	The TMEM216 c.253C>T variant is predicted to result in premature protein termination (p.Arg85*). This variant has been reported in the homozygous state in two fetuses with Meckel-Gruber syndrome from one family (Valente et al 2010. PubMed ID: 20512146). This variant has also been reported in the homozygous or heterozygous states in individuals with Joubert syndrome (Bachmann-Gagescu et al. 2015. PubMed ID: 26092869. Table S5; Summers et al. 2017. PubMed ID: 28497568. Table S2; Szymanska et al. 2012. PubMed ID: 23351400). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-61165269-C-T). Nonsense variants in TMEM216 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV000201650	SCV004206190	pathogenic	Joubert syndrome 2	2023-10-31	criteria provided, single submitter	clinical testing
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.