ClinVar Genomic variation as it relates to human health

ClinVar contains an entry for this variant (Variation ID: 216826). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 26092869, 27491411, 28719906). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs775883520, gnomAD 0.003%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 242 of the TMEM67 protein (p.Asn242Ser). 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. For these reasons, this variant has been classified as Pathogenic.

The homozygous p.Asn242Ser variant in TMEM67 was identified by our study in one individual with Joubert syndrome. The p.Asn242Ser variant in TMEM67 was reported in 23 individuals (including 22 Iranians) with Joubert syndrome, segregated with disease in 22 affected relatives from 9 families (PMID: 28719906, 19574260), and has been identified in 0.002978% (1/33580) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs775883520). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency and its prevalence in Iranian families with a shared haplotype suggests this is a founder variant (PMID: 28719906). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant was also reported likely pathogenic in ClinVar prior to the publication of a paper about 22 Iranians from 9 families with this variant and Joubert syndrome (Variation ID: 216826). Two additional variants at the the same position, p.Asn242Thr and p.Asn242Lys, have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 23559409, 19574260). Position 242 in the TMEM67 protein has also been reported as a glycosylation site for GlcNAc, providing additional support that a change in this position may not be tolerated (Entry: Q5HYA8) In summary, this variant meets criteria to be classified as pathogenic for Joubert syndrome in an autosomal recessive manner based on the predicted impact of a change at position 242 in TMEM67 and cosegregation with Joubertssyndrome in multiple Iranian families. ACMG/AMP Criteria applied: PM2, PP3, PM5, PM1_Supporting, PP1_Strong (Richards 2015).

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.91). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000216826). Different missense changes at the same codon (p.Asn242Lys, p.Asn242Thr) have been reported to be associated with TMEM67 -related disorder (PMID: 19574260 , 23559409). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26260382, 29302074, 25920555, 26092869, 30315573, 32000717, 33726816, 35032046, 28719906, 27491411)

A generation of sequencing tests were performed on the foetus's parents and the prior witness: the father carried c. 475 T >C;Het, mother carrying c. 725A> G;Het, daughter carrying c. 475 T >C; c. 725A> G double heterozygous, the fetus and the first witness inherited the genetic mutations of both parents