rs878853113
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000304.4(PMP22):c.245T>C(p.Leu82Pro) 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L82L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
PMP22
NM_000304.4 missense
NM_000304.4 missense
Scores
7
5
4
Clinical Significance
Conservation
PhyloP100: 6.02
Genes affected
PMP22 (HGNC:9118): (peripheral myelin protein 22) This gene encodes an integral membrane protein that is a major component of myelin in the peripheral nervous system. Studies suggest two alternately used promoters drive tissue-specific expression. Various mutations of this gene are causes of Charcot-Marie-Tooth disease Type IA, Dejerine-Sottas syndrome, and hereditary neuropathy with liability to pressure palsies. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000304.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.876
PP5
?
Variant 17-15239545-A-G is Pathogenic according to our data. Variant chr17-15239545-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235779.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMP22 | NM_000304.4 | c.245T>C | p.Leu82Pro | missense_variant | 4/5 | ENST00000312280.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMP22 | ENST00000312280.9 | c.245T>C | p.Leu82Pro | missense_variant | 4/5 | 1 | NM_000304.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 13, 2016 | The L82P pathogenic variant in the PMP22 gene has been reported previously as a de novo variant in an individual with Charcot-Marie-Tooth disease type 1E (Kim et al., 2016). The L82P variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L82P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. However, in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (L78P, S79T, S79P, S79C, L80R, L80P) have been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth disease or Dejerine-Sottas disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret L82P as a pathogenic variant. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Mar 20, 2015 | - - |
Charcot-Marie-Tooth disease, type I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2019 | This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 82 of the PMP22 protein (p.Leu82Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant has not been reported in the literature in individuals with PMP22-related conditions. ClinVar contains an entry for this variant (Variation ID: 235779). 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. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
DEOGEN2
Pathogenic
D;D;D;D;D;.;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;.;.;.;D;D;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
T
Sift4G
Uncertain
D;D;D;.;D;.;.;.;D
Polyphen
D;D;D;.;.;.;.;.;.
Vest4
MutPred
Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);.;.;Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);
MVP
MPC
1.4
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at