Submissions for variant NM_153704.6(TMEM67):c.245C>G (p.Pro82Arg)

dbSNP: rs772437766

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201553	SCV000256503	pathogenic	Joubert syndrome 6	2015-02-23	criteria provided, single submitter	research
GeneDx	RCV000435911	SCV000515815	pathogenic	not provided	2015-09-17	criteria provided, single submitter	clinical testing	The P82R variant has been reported previously in combination with the M252T variant in individuals withCOACH syndrome and Joubert syndrome related disorder (JSRD) without clinically apparent liver disease(Doherty et al., 2010). It was not observed in approximately 6,500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant inthese populations. The P82R variant is a non-conservative amino acid substitution, which is likely to impactsecondary protein structure as these residues differ in polarity, charge, size and/or other properties. Thissubstitution occurs at a position that is conserved across species. Additionally, a different missense variant atthe same residue (P82S) and in a nearby residue (N90K) have been reported in association with TMEM67-related disorders, supporting the functional importance of this region of the protein (Doherty et al., 2010;Iannicelli et al., 2010). We interpret P82R as a pathogenic variant.
SIB Swiss Institute of Bioinformatics	RCV000201553	SCV000803599	uncertain significance	Joubert syndrome 6	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Joubert syndrome 6, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:19574260).
Invitae	RCV003765306	SCV004570134	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2023-01-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro82 amino acid residue in TMEM67. Other variant(s) that disrupt this residue have been observed in individuals with TMEM67-related conditions (PMID: 19574260, 29568536), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 217714). This missense change has been observed in individual(s) with TMEM67-related conditions (PMID: 19574260, 29568536). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 82 of the TMEM67 protein (p.Pro82Arg).