ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate a damaging effect on MPZ protein properties in vitro (Raasakka et al., 2019).; In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12207932, 15716547, 26310628, 20800346, 28364294, 21336783, 29687021, 31173589, 33179255, 32376792, 20461396, 33359733)

This variant, c.706_708del, results in the deletion of 1 amino acid(s) of the MPZ protein (p.Lys236del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs755446743, gnomAD 0.006%). This variant has been observed in individuals with late-onset Charcot-Marie-Tooth disease (PMID: 12207932, 15716547). It has also been observed to segregate with disease in related individuals. This variant is also known as K263Del. ClinVar contains an entry for this variant (Variation ID: 447734). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MPZ function (PMID: 29687021, 31173589). For these reasons, this variant has been classified as Pathogenic.

The c.706_708delAAG (p.K236del) alteration is located in exon 6 (coding exon 6) of the MPZ gene. This alteration consists of an in-frame deletion of 3 nucleotides between nucleotide positions c.706 and c.708, resulting in the deletion of the lysine residue at codon 236. This alteration has been previously reported in multiple families with features of autosomal dominant, adult onset Charcot-Marie-Tooth disease; however, the phenotype reported in one family shows variable penetrance with symptoms ranging from being asymptomatic to having foot deformities, pedal numbness, and muscle cramps (Street, 2002; Sowden, 2005; Volodarsky, 2021). This amino acid position is highly conserved in available vertebrate species. Overall, functional studies suggest that the protein is mislocalized to the cytoplasm, alters protein-lipid interactions, and activates the unfolded protein response in vitro; however, additional evidence is needed to confirm these results (Bai, 2018; Raasakka, 2019). This alteration is predicted to be neutral by in silico analysis (Choi, 2012). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

The p.Lys236del (historically referred to as K207del or K263Del) variant in MPZ has been reported in 4 individuals with late-onset Charcot-Marie-Tooth disease and segregated with disease in two relatives (Street 2002 PubMed: 12207932, Volodarsky 2021 PubMed: 32376792; Sowden 2005 PMID: 15716547). This variant is an in-frame 1-amino acid deletion. It has also been reported by other clinical laboratories in ClinVar (Variation ID 447734) and detected in 1/64552 non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD, http://exac.broadinstitute.org). Functional data demonstrates that this variant affects protein function (Bai 2018 PubMed: 29687021). In summary, this variant is likely pathogenic for Charcot-Marie-Tooth disease in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Supporting, PM2_Supporting, PM4_Supporting, PS3_Moderate, PP1.

This sequence variant is a three nucleotide deletion (delAAG) at positions 706_708 of the coding MPZ gene and results in the deletion of the Lys236 codon. The 236 residue falls in the cytoplasmic tail which contributes to the physical properties of the myelin lipid membrane (PMID: 31173589). This is a previously reported variant (ClinVar 447734) that has been observed in individuals affected by Charcot–Marie–Tooth disease (PMID: 32376792, 33179255, 26310628, 36203352) and has been found to segregate with this disorder in two families (PMID: 12207932, 12207932). This variant is present in 35 of 1,613,628 alleles (0.002%) in the gnomAD v4.0.0 population dataset. Predictions from bioinformatic tools are inconclusive for this variant, and the Lys236 residue at this position is conserved across the vertebrate species examined. In vitro analysis indicates that this variant significantly disrupts the lipid membrane structure of myelin (PMID: 31173589). Based upon the evidence, we consider this a pathogenic variant. ACMG Criteria: PM2, PM4, PS3, PS4

PP1, PM1, PM2, PS3_supporting, PS4_supporting

Variant interpretted as Uncertain significance and reported on 07/27/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.