ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.245C>G (p.Pro82Arg) (rs772437766)

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Total submissions: 3
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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).

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