rs104894617

Positions:

• chr17-15260681-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 5.44

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a transmembrane_region Helical (size 29) in uniprot entity PMP22_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) 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 id is 8428.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-15260681-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMP22	NM_000304.4	c.47T>C	p.Leu16Pro	missense_variant	2/5	ENST00000312280.9	NP_000295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMP22	ENST00000312280.9	c.47T>C	p.Leu16Pro	missense_variant	2/5	1	NM_000304.4	ENSP00000308937.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1401100 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 691218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.00212 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1993	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 11, 2019

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). This variant is not present in population databases (ExAC no frequency). 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. 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). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
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	D
LIST_S2	Benign	0.70	T;.;.;.;.;T;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	2.9	M;M;M;.;.;.;.
PrimateAI	Pathogenic	0.83	D
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	D
GERP RS		3.4
Varity_R		0.77
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: rs104894617; hg19: chr17-15163998;