Submissions for variant NM_001173990.3(TMEM216):c.398T>G (p.Leu133Ter)

gnomAD frequency: 0.00003  dbSNP: rs755459875

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201555	SCV000256483	pathogenic	Joubert syndrome 2	2015-02-23	criteria provided, single submitter	research
GeneDx	RCV000443367	SCV000521240	likely pathogenic	not provided	2018-10-29	criteria provided, single submitter	clinical testing	The L133X variant in the TMEM216 gene has been reported previously, along with a TMEM216 missense variant, in individuals with clinical findings of Joubert syndrome (Valente et al., 2010; Bachmann-Gagescu et al., 2015). This variant is predicted to cause loss of normal protein function through protein truncation. The L133X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret L133X as a likely pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000201555	SCV002014850	pathogenic	Joubert syndrome 2	2021-10-10	criteria provided, single submitter	clinical testing	Variant summary: TMEM216 c.398T>G (p.Leu133X) 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 8e-06 in 249212 control chromosomes. c.398T>G has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Joubert Syndrome 2 and has been subsequently cited by others (example, Valente_2010, Bachmann-Gagescu_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001853240	SCV002200618	pathogenic	Familial aplasia of the vermis	2023-07-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu133*) in the TMEM216 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 13 amino acid(s) of the TMEM216 protein. This variant is present in population databases (rs755459875, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome (PMID: 20512146, 26092869). ClinVar contains an entry for this variant (Variation ID: 217704). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002503792	SCV002811738	likely pathogenic	Joubert syndrome 2; Meckel syndrome, type 2	2022-04-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003907755	SCV004735933	pathogenic	TMEM216-related condition	2024-01-29	criteria provided, single submitter	clinical testing	The TMEM216 c.398T>G variant is predicted to result in premature protein termination (p.Leu133*). This variant has been identified in two presumably unrelated individuals with Joubert syndrome and related disorders (Valente et al. 2010. PubMed ID: 20512146; Bachmann-Gagescu et al. 2015. PubMed ID: 26092869). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in TMEM216 are expected to be pathogenic. This variant is interpreted as pathogenic.