ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.208C>G (p.Pro70Ala) (rs878853697)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000231475 SCV000283686 pathogenic Charcot-Marie-Tooth Neuropathy X 2017-06-26 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 70 of the GJB1 protein (p.Pro70Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Charcot-Marie-Tooth disease type 1X (CMT1X) in a single family (PMID: 10873293). This variant has also been reported in multiple unrelated individuals affected with CMT1X (PMID: 21692908, Invitae). ClinVar contains an entry for this variant (Variation ID: 237122). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000484101 SCV000565042 likely pathogenic not provided 2016-08-01 criteria provided, single submitter clinical testing The P70A variant has been previously reported in association with a mild Charcot-Marie-Tooth phenotype (Ionasescu et al., 1998; Siskind et al., 2011). A different missense variant at the same residue (P70S) has also been reported in a female with CMTX1 (Houlden et al., 2009; Stenson et al., 2014). Additionally, missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with CMTX1 (Stenson et al., 2014), supporting the functional importance of this region of the protein. It was not observed in approximately 6,500 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 P70A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Inherited Neuropathy Consortium RCV000789229 SCV000928581 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.