Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000807479 | SCV000947532 | pathogenic | Charcot-Marie-Tooth disease, type I | 2022-11-17 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PMP22 function (PMID: 26102530, 28748849). 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 C0"). ClinVar contains an entry for this variant (Variation ID: 637376). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 9040744, 28286897; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 107 of the PMP22 protein (p.Gly107Val). |
| Ambry Genetics | RCV002535805 | SCV003668892 | likely pathogenic | Inborn genetic diseases | 2023-01-03 | criteria provided, single submitter | clinical testing | The c.320G>T (p.G107V) alteration is located in exon 5 (coding exon 4) of the PMP22 gene. This alteration results from a G to T substitution at nucleotide position 320, causing the glycine (G) at amino acid position 107 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in multiple individuals with features consistent with or clinical diagnoses of Charcot-Marie-Tooth (CMT) disease (Hanemann, 2000; Lorefice, 2017; Liu, 2020, Invitae pers. comm.; Ambry internal data) and was shown to segregate with disease in one multigenerational family with several affected individuals (Marrosu, 1997). In HeLa cells, this variant co-localized with calnexin in reticular endoplasmic reticulum-like structures as well as in intracellular aggregates compared to wild type which localized to the plasma membrane (Shames, 2003). Another study observed a similar pattern of endoplasmic reticulum localization for this variant (Li, 2017). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. |
| Inherited Neuropathy Consortium | RCV000789517 | SCV000928873 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |