ClinVar Miner

Submissions for variant NM_000304.4(PMP22):c.124T>C (p.Cys42Arg)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3billion, Medical Genetics RCV003152871 SCV003841350 uncertain significance Charcot-Marie-Tooth disease, type IA 2023-02-23 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PMP22 related disorder (PMID: 27549087). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp RCV003581894 SCV004296754 uncertain significance Charcot-Marie-Tooth disease, type I 2024-06-17 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 42 of the PMP22 protein (p.Cys42Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary neuropathy with liability to pressure palsies and/or PMP22-related conditions (PMID: 27549087, 29127354). ClinVar contains an entry for this variant (Variation ID: 2444073). 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 expected to disrupt PMP22 protein function with a positive predictive value of 95%. 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.

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