Submissions for variant NM_153704.6(TMEM67):c.2848G>A (p.Val950Met)

gnomAD frequency: 0.00004  dbSNP: rs771551765

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000429127	SCV000536258	uncertain significance	not provided	2017-01-19	criteria provided, single submitter	clinical testing	The V950M variant in the TMEM67 gene has been reported previously in the homozygous state in siblings with intellectual disability, physical weakness, deafness and speech problems. The parents and siblings heterozygous for the V950M variant were unaffected (Riazuddin et al., 2016). The V950M variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V950M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V950M as a variant of uncertain significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000984518	SCV001132575	likely pathogenic	Joubert syndrome 6	2018-11-15	criteria provided, single submitter	research	The homozygous p.Val950Met variant in TMEM67 was identified by our study in two individuals with Joubert Syndrome. This variant has been identified in the literature in one homozygous proband, and later in the literature in another homozygous proband (Minami et al. 1999, PMID: 10567047; Riazuddin et al. 2017, PMID: 27457812). This variant has been identified in <0.01% (1/33538) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs771551765). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic.
Invitae	RCV001851095	SCV002110755	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 950 of the TMEM67 protein (p.Val950Met). This variant is present in population databases (rs771551765, gnomAD 0.003%). This missense change has been observed in individual(s) with intellectual disability (PMID: 27457812). ClinVar contains an entry for this variant (Variation ID: 392916). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics	RCV002248661	SCV002516094	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing