Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000691854 | SCV000819650 | likely pathogenic | Charcot-Marie-Tooth Neuropathy X | 2020-01-07 | criteria provided, single submitter | clinical testing | This variant has been reported in individual(s) with clinical features of Charcot-Marie-Tooth (CMT) disease (PMID: 24078732, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 570878). This variant is not present in population databases (ExAC no frequency). 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 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. This variant disrupts the p.Val177 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 10586284, 20491857, 9856562), which suggests that this may be a clinically significant amino acid residue. This sequence change replaces valine with methionine at codon 177 of the GJB1 protein (p.Val177Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. |
| ARUP Laboratories, |
RCV005231278 | SCV005878677 | likely pathogenic | Charcot-Marie-Tooth disease X-linked dominant 1 | 2024-10-25 | criteria provided, single submitter | clinical testing | The GJB1 c.529G>A; p.Val177Met variant (rs1569215351, ClinVar Variation ID: 570878) is reported in the literature in two individuals with clinical features consistent with Charcot-Marie-Tooth disease (Record 2023, Sivera 2013). Additionally this variant was found to segregate with disease (external communications). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, other variants at this codon (c.530T>C, p.Val177Ala; c.529G>A, p.Val177Leu) have been reported in individuals with Charcot-Marie-Tooth disease (Ikegami 1998, Record 2023). Computational analyses predict that this variant is deleterious (REVEL: 0.96). Based on available information, this variant is considered to be likely pathogenic. References: Ikegami T et al. Four novel mutations of the connexin 32 gene in four Japanese families with Charcot-Marie-Tooth disease type 1. Am J Med Genet. 1998 Dec 4;80(4):352-5. PMID: 9856562. Record CJ et al. Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants. Brain. 2023 Oct 3;146(10):4336-4349. PMID: 37284795. Sivera R et al. Charcot-Marie-Tooth disease: genetic and clinical spectrum in a Spanish clinical series. Neurology. 2013 Oct 29;81(18):1617-25. PMID: 24078732. |
| Inherited Neuropathy Consortium | RCV000789941 | SCV000929326 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |