Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001210532 | SCV001382024 | uncertain significance | Charcot-Marie-Tooth Neuropathy X | 2019-10-12 | criteria provided, single submitter | clinical testing | 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. This variant has been observed in several individuals affected with Charcot-Marie-Tooth disease or hereditary motor and sensory neuropathy (PMID: 16096811, Invitae). ClinVar contains an entry for this variant (Variation ID: 637180). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with serine at codon 175 of the GJB1 protein (p.Asn175Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. This variant disrupts the p.Asn175 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 9633821), which suggests that this may be a clinically significant amino acid residue. |
| Inherited Neuropathy Consortium | RCV000789239 | SCV000928591 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |