rs104894617

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_000304.4(PMP22):c.47T>C(p.Leu16Pro) 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 Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PMP22
NM_000304.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 5.44

Publications

69 publications found

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]

PMP22 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease type 1A
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Ambry Genetics
hereditary neuropathy with liability to pressure palsies
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
Charcot-Marie-Tooth disease type 1E
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PMP22 links:

ENSG00000279660 (HGNC:):

ENSG00000279660 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000304.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.887

PP5

Variant 17-15260681-A-G is Pathogenic according to our data. Variant chr17-15260681-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 8428.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMP22	NM_000304.4 link	c.47T>C	p.Leu16Pro	missense_variant	Exon 2 of 5	ENST00000312280.9	NP_000295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMP22	ENST00000312280.9 link	c.47T>C	p.Leu16Pro	missense_variant	Exon 2 of 5	1	NM_000304.4	ENSP00000308937.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1401100

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691218

African (AFR)

AF:

0.00

AC:

AN:

31702

American (AMR)

AF:

0.00

AC:

AN:

35898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25192

East Asian (EAS)

AF:

0.00

AC:

AN:

35892

South Asian (SAS)

AF:

0.00

AC:

AN:

79292

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079900

Other (OTH)

AF:

0.00

AC:

AN:

58106

GnomAD4 genome

Cov.:

Alfa

AF:

0.00212

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease, type IA

Pathogenic:1Other:1

May 01, 1993

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

- -

Charcot-Marie-Tooth disease, type I

Pathogenic:1

Jul 11, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine with proline at codon 16 of the PMP22 protein (p.Leu16Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change results in an unstable, improperly folded and mislocalized protein (PMID: 26102530, 18795802, 21827951, 25385046, 9425015). Furthermore, mouse models with this missense change recapitulate the human phenotype (PMID: 6313869, 12090404). This variant has been reported to be de novo in an individual affected with¬†Charcot-Marie-Tooth disease, type 1 (CMT1) (PMID: 8995589) and has been reported to segregate with CMT1 in affected families (PMID: 8995589, 1303281). It has also been reported in an unrelated individual affected with CMT1 (PMID: 23689413). ClinVar contains an entry for this variant (Variation ID: 8428). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Benign

0.92

DEOGEN2

Pathogenic

0.94

D;D;D;D;D;D;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.70

T;.;.;.;.;T;T

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.89

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.57

MutationAssessor

Pathogenic

2.9

M;M;M;.;.;.;.

PhyloP100

5.4

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.8

.;D;D;.;D;.;D

REVEL

Pathogenic

0.80

Sift

Benign

0.077

.;T;T;.;D;.;T

Sift4G

Uncertain

0.035

D;D;D;.;D;.;D

Polyphen

0.93

P;P;P;.;.;.;.

Vest4

0.93

MutPred

0.73

Loss of stability (P = 0.0826);Loss of stability (P = 0.0826);Loss of stability (P = 0.0826);Loss of stability (P = 0.0826);Loss of stability (P = 0.0826);Loss of stability (P = 0.0826);Loss of stability (P = 0.0826);

MVP

0.98

MPC

1.2

ClinPred

0.98

GERP RS

3.4

PromoterAI

0.025

Neutral

(source)

Varity_R

0.77

gMVP

0.98

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over