ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.372G>C (p.Lys124Asn) (rs876661119)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000216227 SCV000279581 likely pathogenic not provided 2017-06-23 criteria provided, single submitter clinical testing The K124N variant in the GJB1 gene has been reported previously in association with X-linked Charcot-Marie-Tooth disease (CMTX) (Bone et al., 1997). The K124N variant 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 K124N 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 where amino acids with similar properties to Lysine are tolerated across species and is predicted to be within the intracellular loop between the second and third transmembrane regions of the GJB1 protein (Bone et al., 1997; Kleopa et al., 2012). Multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with GJB1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. This variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV001294422 SCV001483300 uncertain significance Charcot-Marie-Tooth Neuropathy X 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 124 of the GJB1 protein (p.Lys124Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 9361298, Invitae). ClinVar contains an entry for this variant (Variation ID: 234611). 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: Benign; Align-GVGD: Class C). This variant disrupts the p.Lys124 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 27234031), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 6
Inherited Neuropathy Consortium RCV000789170 SCV000928522 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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