rs104894626
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000304.4(PMP22):c.82T>C(p.Trp28Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000304.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PMP22 | NM_000304.4 | c.82T>C | p.Trp28Arg | missense_variant | Exon 3 of 5 | ENST00000312280.9 | NP_000295.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 1E Pathogenic:1Other:1
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not provided Pathogenic:1
Reported heterozygous in siblings with Charcot-Marie-Tooth disease type 1 and deafness in published literature (PMID: 11835375); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34332267, 25400662, 28374912, 11545686, 11835375, 29038142) -
Charcot-Marie-Tooth disease, type I Pathogenic:1
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 28 of the PMP22 protein (p.Trp28Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Charcot-Marie-Tooth disease (PMID: 11835375; Invitae). ClinVar contains an entry for this variant (Variation ID: 8440). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Trp28 amino acid residue in PMP22. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 34332267; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at