17-15239591-C-G

Variant names:

• chr17-15239591-C-G
• rs104894623
• NM_000304.4:c.199G>C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000304.4(PMP22):​c.199G>C​(p.Ala67Pro) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A67D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMP22 NM_000304.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.77

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.

• 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 chr17-15239590-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-15239591-C-G is Pathogenic according to our data. Variant chr17-15239591-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-15239591-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMP22	NM_000304.4	c.199G>C	p.Ala67Pro	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.199G>C	p.Ala67Pro	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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 1E Pathogenic:1 Other:1

Jun 01, 1999

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

- -

not provided Pathogenic:1

Dec 20, 2019

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Very strong co-segregation with disease in affected individuals from a single family. -

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

May 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is also known as 248G>C. This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 67 of the PMP22 protein (p.Ala67Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease and Charcot-Marie-Tooth disease and deafness (PMID: 10330345, 11920834; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8436). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.98	D;D;D;D;D;D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;.;.;.;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.6	M;M;M;.;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.8	.;D;D;.;D;.;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	.;D;D;.;D;.;D
Sift4G	Uncertain	0.0050	D;D;D;.;D;.;D
Polyphen		1.0	D;D;D;.;.;.;.
Vest4		0.95
MutPred		0.95		Gain of disorder (P = 0.0878);Gain of disorder (P = 0.0878);Gain of disorder (P = 0.0878);Gain of disorder (P = 0.0878);Gain of disorder (P = 0.0878);Gain of disorder (P = 0.0878);Gain of disorder (P = 0.0878);
MVP		0.97
MPC		1.3
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.99

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: rs104894623; hg19: chr17-15142908;