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

Genomes: not found (cov: 31)

Consequence

PMP22
NM_000304.4 missense

Scores

13
3
3

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 4.89
Variant links:
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 Pathogenic. Variant got 16 ACMG points.

PM1
In a transmembrane_region Helical (size 29) in uniprot entity PMP22_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000304.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant 17-15259190-A-G is Pathogenic according to our data. Variant chr17-15259190-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-15259190-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PMP22NM_000304.4 linkc.82T>C p.Trp28Arg missense_variant Exon 3 of 5 ENST00000312280.9 NP_000295.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PMP22ENST00000312280.9 linkc.82T>C p.Trp28Arg missense_variant Exon 3 of 5 1 NM_000304.4 ENSP00000308937.3 Q01453

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 1E Pathogenic:1Other:1
Feb 01, 2002
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

not provided Pathogenic:1
Feb 26, 2024
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Oct 07, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
29
DANN
Benign
0.95
DEOGEN2
Pathogenic
0.98
D;D;D;D;D;D;.
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.73
T;.;.;.;.;T;T
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.2
D
MutationAssessor
Pathogenic
3.4
M;M;M;.;.;.;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-14
.;D;D;.;D;.;D
REVEL
Pathogenic
0.89
Sift
Pathogenic
0.0
.;D;D;.;D;.;D
Sift4G
Pathogenic
0.0
D;D;D;.;D;.;D
Polyphen
1.0
D;D;D;.;.;.;.
Vest4
0.94
MutPred
0.94
Gain of methylation at W28 (P = 0.0346);Gain of methylation at W28 (P = 0.0346);Gain of methylation at W28 (P = 0.0346);Gain of methylation at W28 (P = 0.0346);Gain of methylation at W28 (P = 0.0346);Gain of methylation at W28 (P = 0.0346);Gain of methylation at W28 (P = 0.0346);
MVP
1.0
MPC
1.8
ClinPred
1.0
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.94
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104894626; hg19: chr17-15162507; API