Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ce |
RCV000994158 | SCV001147496 | uncertain significance | not provided | 2019-06-01 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV000994158 | SCV001473459 | uncertain significance | not provided | 2020-04-04 | criteria provided, single submitter | clinical testing | The MPZ c.199C>T; p.Arg67Cys variant (rs775361544) is reported in the literature in two siblings affected with Charcot-Marie-Tooth disease, as well as their asymptomatic mother (Young 2013). However, both affected siblings also carried a PMP22 duplication that was also found in a third affected sibling who did not carry p.Arg67Cys. The p.Arg67Cys variant is found on only seven chromosomes (7/282678 alleles) in the Genome Aggregation Database. The arginine at codon 67 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. . Other amino acid substitutions at this codon (p.Arg67His, p.Arg67Pro) have been reported in individuals with symptoms of CMT; however, the clinical significance of these variants in disease is uncertain (Hisama 2005, Antoniadi 2015). Given the lack of clinical and functional data, the significance of the p.Arg67Cys variant is uncertain at this time. References: Antoniadi T et al. Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability. BMC Med Genet. 2015 Sep 21;16:84. Hisama FM. Familial periodic paralysis and Charcot-Marie-Tooth disease in a 7-generation family. Arch Neurol. 2005 Jan;62(1):135-8. Young T et al. Compound Charcot-Marie-Tooth disease: a kindred with severe hereditary neuropathy, pupil abnormalities and a novel MPZ mutation. J Neurol Neurosurg Psychiatry. 2013 Feb;84(2):234-6. |
| Invitae | RCV002536920 | SCV003019894 | uncertain significance | Charcot-Marie-Tooth disease, type I | 2022-10-13 | criteria provided, single submitter | clinical testing | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MPZ protein function. ClinVar contains an entry for this variant (Variation ID: 637803). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 23197742). This variant is present in population databases (rs775361544, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 67 of the MPZ protein (p.Arg67Cys). This variant disrupts the p.Arg67 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15642860, 26392352, 32376792; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Inherited Neuropathy Consortium | RCV000790124 | SCV000929515 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |