ClinVar Miner

Submissions for variant NM_018972.4(GDAP1):c.376G>A (p.Glu126Lys) (rs879254005)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236743 SCV000293140 uncertain significance not provided 2015-09-17 criteria provided, single submitter clinical testing The E126K variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. 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 E126K variant is a non-conservative amino acid substitution, 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 in mammals, and multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with Charcot-Marie Tooth disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. Specifically, R120W and H123R have been associated with autosomal dominant CMT (Zimon et al., 2011). In silico analysis is inconsistent in its predictions as to whether or not the E126K variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000805046 SCV000944989 likely pathogenic Charcot-Marie-Tooth disease, type 4A 2019-04-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 126 of the GDAP1 protein (p.Glu126Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with autosomal dominant Charcot-Marie-Tooth disease and has been observed to segregate with disease in a family (PMID: 28244113, Invitae). ClinVar contains an entry for this variant (Variation ID: 245933). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.

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