17-15231073-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000304.4(PMP22):​c.327C>A​(p.Cys109*) variant causes a stop gained 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C109C) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Consequence

PMP22
NM_000304.4 stop_gained

Scores

1
6

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: -1.64
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 21 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-15231073-G-T is Pathogenic according to our data. Variant chr17-15231073-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 217237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-15231073-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PMP22NM_000304.4 linkc.327C>A p.Cys109* stop_gained Exon 5 of 5 ENST00000312280.9 NP_000295.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PMP22ENST00000312280.9 linkc.327C>A p.Cys109* stop_gained Exon 5 of 5 1 NM_000304.4 ENSP00000308937.3 Q01453

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Dec 27, 2018
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. Moderate co-segregation with disease in affected individuals from a single family. -

Jul 17, 2019
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23224996, 15099590, 22131320, 32376792) -

Charcot-Marie-Tooth disease Pathogenic:1
-
Molecular Genetics Laboratory, London Health Sciences Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease, type I Pathogenic:1
Jan 24, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Cys109*) in the PMP22 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acid(s) of the PMP22 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with neuropathy (PMID: 15099590, 22131320). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217237). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Benign
-0.36
CADD
Pathogenic
26
DANN
Benign
0.92
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.31
N
Vest4
0.89
GERP RS
-10
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7

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: rs863225028; hg19: chr17-15134390; API