Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_153704.6(TMEM67):βc.579_580delβ(p.Gly195IlefsTer13) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000145 in 1,611,002 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
TMEM67 (HGNC:28396): (transmembrane protein 67) The protein encoded by this gene localizes to the primary cilium and to the plasma membrane. The gene functions in centriole migration to the apical membrane and formation of the primary cilium. Multiple transcript variants encoding different isoforms have been found for this gene. Defects in this gene are a cause of Meckel syndrome type 3 (MKS3) and Joubert syndrome type 6 (JBTS6). [provided by RefSeq, Nov 2008]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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PVS1 - null variant (nonsense, frameshift, canonical Β±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
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PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 8-93765573-CAG-C is Pathogenic according to our data. Variant chr8-93765573-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-93765573-CAG-C is described in Lovd as [Pathogenic]. Variant chr8-93765573-CAG-C is described in Lovd as [Likely_pathogenic].
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
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not provided Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
May 30, 2017
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Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Jan 31, 2023
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) -
Joubert syndrome 6 Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Genetic Services Laboratory, University of Chicago
Jun 18, 2014
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Pathogenic, criteria provided, single submitter
research
UW Hindbrain Malformation Research Program, University of Washington
Feb 23, 2015
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Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Dec 13, 2023
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. -
Joubert syndrome and related disorders Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Nov 30, 2023
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. -
TMEM67-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Apr 28, 2017
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. -