Submissions for variant NM_000304.4(PMP22):c.206T>A (p.Met69Lys)

dbSNP: rs104894620

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494533	SCV000582901	pathogenic	not provided	2017-05-18	criteria provided, single submitter	clinical testing	The M69K missense variant in the PMP22 gene has been reported previously as a de novo change in an individual with Dejerine-Sottas syndrome (Roa et al., 1993). Functional studies have demonstrated that the M69K variant impairs and destabilizes the PMP22 protein (Schleback et al., 2015). The M69K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M69K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants at the same (M69R) in nearby residues (A67T/P/D, L71P, S72P/W/L) have been reported in Human Gene Mutation Database in association with PMP22-related neuropathies (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is interpreted to be a pathogenic variant and its presence is consistent with the diagnosis in this patient.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380437	SCV001578515	pathogenic	Charcot-Marie-Tooth disease, type I	2022-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 69 of the PMP22 protein (p.Met69Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dejerine-Sottas syndrome (PMID: 8275092). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 8432). 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. Experimental studies have shown that this missense change affects PMP22 function (PMID: 26102530). For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV003338380	SCV004047200	pathogenic	Charcot-Marie-Tooth disease, type IA		criteria provided, single submitter	clinical testing	The missense variant c.206T>A (p.Met69Lys) in PMP22 gene has been reported previously in heterozygous state in individuals affected with Charcot-MarieTooth disease, type 1A (Chundi Vinay Kumar et al., 2014). Functional studies have demonstrated that the M69K variant impairs and destabilizes the PMP22 protein (Schleback et al., 2015). The p.Met69Lys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar as Pathogenic. The amino acid Met at position 69 is changed to a Lys changing protein sequence and it might alter its composition and physicochemical properties. The amino acid change p.Met69Lys in PMP22 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000008947	SCV000029157	pathogenic	DEJERINE-SOTTAS SYNDROME, AUTOSOMAL DOMINANT	1993-11-01	no assertion criteria provided	literature only