17-15239584-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000494511.7(PMP22):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMP22 ENST00000494511.7 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.16

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-15239584-A-T is Pathogenic according to our data. Variant chr17-15239584-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 8432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-15239584-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMP22	NM_000304.4	c.206T>A	p.Met69Lys	missense_variant	4/5	ENST00000312280.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMP22	ENST00000312280.9	c.206T>A	p.Met69Lys	missense_variant	4/5	1	NM_000304.4	P1

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

Submissions by phenotype

Charcot-Marie-Tooth disease, type IA Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant c.206T>A (p.Met69Lys) in PMP22 gene has been reported previously in heterozygous state in individuals affected with Charcot-MarieTooth disease, type 1A (Chundi Vinay Kumar et al., 2014). Functional studies have demonstrated that the M69K variant impairs and destabilizes the PMP22 protein (Schleback et al., 2015). The p.Met69Lys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar as Pathogenic. The amino acid Met at position 69 is changed to a Lys changing protein sequence and it might alter its composition and physicochemical properties. The amino acid change p.Met69Lys in PMP22 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 18, 2017

The M69K missense variant in the PMP22 gene has been reported previously as a de novo change in an individual with Dejerine-Sottas syndrome (Roa et al., 1993). Functional studies have demonstrated that the M69K variant impairs and destabilizes the PMP22 protein (Schleback et al., 2015). The M69K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M69K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants at the same (M69R) in nearby residues (A67T/P/D, L71P, S72P/W/L) have been reported in Human Gene Mutation Database in association with PMP22-related neuropathies (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is interpreted to be a pathogenic variant and its presence is consistent with the diagnosis in this patient. -

Dejerine-Sottas syndrome, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1993

- -

Charcot-Marie-Tooth disease, type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2022

ClinVar contains an entry for this variant (Variation ID: 8432). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PMP22 function (PMID: 26102530). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMP22 protein function. This missense change has been observed in individual(s) with Dejerine-Sottas syndrome (PMID: 8275092). 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 methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 69 of the PMP22 protein (p.Met69Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	28
Dann	Benign	0.96
DEOGEN2	Pathogenic	0.98	D;D;D;D;D;.;.;D;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;.;.;.;.;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.3	M;M;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.72	T
Sift4G	Uncertain	0.0040	D;D;D;.;D;.;.;.;D
Polyphen		0.99	D;D;D;.;.;.;.;.;.
Vest4		0.96
MutPred		0.94		Gain of ubiquitination at M69 (P = 0.0219);Gain of ubiquitination at M69 (P = 0.0219);Gain of ubiquitination at M69 (P = 0.0219);Gain of ubiquitination at M69 (P = 0.0219);Gain of ubiquitination at M69 (P = 0.0219);.;.;Gain of ubiquitination at M69 (P = 0.0219);Gain of ubiquitination at M69 (P = 0.0219);
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.98

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

Other links and lift over

dbSNP: rs104894620; hg19: chr17-15142901;