ClinVar Genomic variation as it relates to human health

Observed in the homozygous state or with another variant in the TMEM67 gene in multiple patients with Joubert syndrome and related disorders in published literature (Brancati et al., 2009; Iannicelli et al., 2010; Watson et al., 2016; Summers et al., 2017); Frameshift 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: 20232449, 29146704, 31974414, 28431631, 19058225, 28497568, 12368986, 26729329, 30712878, 26092869, 23559409, 31980526, 33432080, 31589614)

Variant summary: TMEM67 c.579_580delAG (p.Gly195IlefsX13) 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 0.00019 in 251350 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TMEM67 causing Joubert Syndrome And Related Disorders (0.00019 vs 0.0018), allowing no conclusion about variant significance. c.579_580delAG has been reported in the literature in individuals affected with Joubert Syndrome including compound heterozygote genotypes (e.g. Fleming_2017) and in a homozygous fetus from a Meckel syndrome family (e.g. Iannicelli_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20232449, 29146704). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=5) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

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.

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. Loss-of-function variants in TMEM67 are known to be pathogenic (PMID: 20232449, 23559409). This variant is present in population databases (rs386834202, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome, COACH syndrome or Meckel-Gruber syndrome (PMID: 19058225, 20232449, 23559409, 26092869, 26729329, 28431631). ClinVar contains an entry for this variant (Variation ID: 56783). For these reasons, this variant has been classified as Pathogenic.

Converted during submission to Likely pathogenic.