rs786204064

Variant names:

• chr17-15239482-T-C
• rs786204064
• NM_000304.4:c.308A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000304.4(PMP22):​c.308A>G​(p.Gln103Arg) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMP22 NM_000304.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.85

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a chain Peripheral myelin protein 22 (size 159) in uniprot entity PMP22_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000304.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 17-15239482-T-C is Pathogenic according to our data. Variant chr17-15239482-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188095.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMP22	NM_000304.4	c.308A>G	p.Gln103Arg	missense_variant	Exon 4 of 5	ENST00000312280.9	NP_000295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMP22	ENST00000312280.9	c.308A>G	p.Gln103Arg	missense_variant	Exon 4 of 5	1	NM_000304.4	ENSP00000308937.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Jan 06, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Has not been previously published as pathogenic or benign to our knowledge -

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

Sep 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 103 of the PMP22 protein (p.Gln103Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PMP22-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 188095). 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. -

not specified Uncertain:1

Sep 16, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PMP22 c.308A>G (p.Gln103Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.308A>G in individuals affected with PMP22-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 188095). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.97	D;D;D;D;D;.;.;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;.;.;.;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.2	M;M;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.4	.;D;D;.;D;.;.;.;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	.;D;D;.;D;.;.;.;D
Sift4G	Benign	0.067	T;T;T;.;D;.;.;.;T
Polyphen		1.0	D;D;D;.;.;.;.;.;.
Vest4		0.93
MutPred		0.83		Gain of MoRF binding (P = 0.0371);Gain of MoRF binding (P = 0.0371);Gain of MoRF binding (P = 0.0371);Gain of MoRF binding (P = 0.0371);Gain of MoRF binding (P = 0.0371);.;.;Gain of MoRF binding (P = 0.0371);Gain of MoRF binding (P = 0.0371);
MVP		0.97
MPC		1.3
ClinPred		0.97	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.96

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: rs786204064; hg19: chr17-15142799;