chr17-15260692-G-T
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000304.4(PMP22):c.36C>A(p.His12Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H12R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000304.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMP22 | NM_000304.4 | c.36C>A | p.His12Gln | missense_variant | 2/5 | ENST00000312280.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMP22 | ENST00000312280.9 | c.36C>A | p.His12Gln | missense_variant | 2/5 | 1 | NM_000304.4 | P1 | |
ENST00000623265.1 | n.180G>T | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1401358Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 691366
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Roussy-Lévy syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP2,PP3. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 27, 2016 | - - |
Charcot-Marie-Tooth disease, type I Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PMP22 function (PMID: 10078969). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 8434). This missense change has been observed in individual(s) with Dejerine-Sottas neuropathy (PMID: 7728152). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 12 of the PMP22 protein (p.His12Gln). - |
Dejerine-Sottas syndrome, autosomal dominant Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1995 | - - |
Dejerine-Sottas disease Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at