Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000492924 | SCV000581870 | likely pathogenic | not provided | 2017-04-26 | criteria provided, single submitter | clinical testing | A variant that is likely pathogenic has been identified in the GJB1 gene. The K103E variant has beenreported in several unrelated individuals with CMTX1 (Bone et al., 1997; Siskind et al., 2011). TheK103E variant is not observed in large population cohorts (Lek et al., 2016; 1000 GenomesConsortium et al., 2015; Exome Variant Server). The K103E variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ in polarity,charge, size and/or other properties. This substitution occurs at a position that is conserved acrossspecies. In silico analysis predicts this variant is probably damaging to the protein structure/function.Missense variants in nearby residues have been reported in the Human Gene Mutation Database inassociation with CMTX1 (Stenson et al., 2014), supporting the functional importance of this regionof the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benigncannot be excluded. |
| Invitae | RCV000704995 | SCV000833972 | likely pathogenic | Charcot-Marie-Tooth Neuropathy X | 2018-06-12 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine with glutamic acid at codon 103 of the GJB1 protein (p.Lys103Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Charcot-Marie-Tooth disease (PMID: 21692908, Invitae). ClinVar contains an entry for this variant (Variation ID: 429329). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Inherited Neuropathy Consortium | RCV000789185 | SCV000928537 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |