rs104894618

Positions:

• chr17-15239554-G-A
• chr17-15239554-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000304.4(PMP22):​c.236C>T​(p.Ser79Phe) variant causes a missense 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S79C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMP22 NM_000304.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.88

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 10 ACMG points.

• PM1: In a transmembrane_region Helical (size 26) in uniprot entity PMP22_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000304.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-15239554-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 17-15239554-G-A is Pathogenic according to our data. Variant chr17-15239554-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1072721.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMP22	NM_000304.4	c.236C>T	p.Ser79Phe	missense_variant	4/5	ENST00000312280.9	NP_000295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMP22	ENST00000312280.9	c.236C>T	p.Ser79Phe	missense_variant	4/5	1	NM_000304.4	ENSP00000308937	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 18, 2022

This variant disrupts the p.Ser79 amino acid residue in PMP22. Other variant(s) that disrupt this residue have been observed in individuals with PMP22-related conditions (PMID: 8510709, 9452053, 22006697), which suggests that this may be a clinically significant amino acid residue. This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 79 of the PMP22 protein (p.Ser79Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1072721). 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. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.96	D;D;D;D;D;.;.;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;.;.;.;.;D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.1	M;M;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.7	.;D;D;.;D;.;.;.;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0040	.;D;D;.;D;.;.;.;D
Sift4G	Uncertain	0.0020	D;D;D;.;D;.;.;.;D
Polyphen		0.97	D;D;D;.;.;.;.;.;.
Vest4		0.80
MutPred		0.79		Loss of catalytic residue at S79 (P = 0.0075);Loss of catalytic residue at S79 (P = 0.0075);Loss of catalytic residue at S79 (P = 0.0075);Loss of catalytic residue at S79 (P = 0.0075);Loss of catalytic residue at S79 (P = 0.0075);.;.;Loss of catalytic residue at S79 (P = 0.0075);Loss of catalytic residue at S79 (P = 0.0075);
MVP		0.95
MPC		1.4
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.57
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-15142871;