Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5
The NM_153704.6(TMEM67):c.1321C>T(p.Arg441Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R441H) has been classified as Likely pathogenic.
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 Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
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;
PM5
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PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr8-93786256-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 972688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
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PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.953
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 8-93786255-C-T is Pathogenic according to our data. Variant chr8-93786255-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217725.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Likely_pathogenic=3, Uncertain_significance=1}. Variant chr8-93786255-C-T is described in Lovd as [Pathogenic].
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Nov 28, 2023
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 441 of the TMEM67 protein (p.Arg441Cys). This variant is present in population databases (rs752362727, gnomAD 0.006%). This missense change has been observed in individual(s) with TMEM67-related conditions (PMID: 19574260, 23351400). ClinVar contains an entry for this variant (Variation ID: 217725). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMEM67 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg441 amino acid residue in TMEM67. Other variant(s) that disrupt this residue have been observed in individuals with TMEM67-related conditions (PMID: 20232449), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -