rs878853113

Positions:

• chr17-15239545-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The ENST00000312280.9(PMP22):​c.245T>C​(p.Leu82Pro) 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L82L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMP22 ENST00000312280.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 6.02

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 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in ENST00000312280.9
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876
• PP5: Variant 17-15239545-A-G is Pathogenic according to our data. Variant chr17-15239545-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235779.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMP22	NM_000304.4	c.245T>C	p.Leu82Pro	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.245T>C	p.Leu82Pro	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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2016	The L82P pathogenic variant in the PMP22 gene has been reported previously as a de novo variant in an individual with Charcot-Marie-Tooth disease type 1E (Kim et al., 2016). The L82P variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L82P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. However, in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (L78P, S79T, S79P, S79C, L80R, L80P) have been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth disease or Dejerine-Sottas disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret L82P as a pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 20, 2015	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 82 of the PMP22 protein (p.Leu82Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant has not been reported in the literature in individuals with PMP22-related conditions. ClinVar contains an entry for this variant (Variation ID: 235779). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.94	D;D;D;D;D;.;.;D;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T;.;.;.;.;D;D;T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.9	L;L;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.0	.;D;D;.;D;.;.;.;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.013	.;D;D;.;D;.;.;.;D
Sift4G	Uncertain	0.0080	D;D;D;.;D;.;.;.;D
Polyphen		1.0	D;D;D;.;.;.;.;.;.
Vest4		0.92
MutPred		0.65		Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);.;.;Loss of stability (P = 0.0247);Loss of stability (P = 0.0247);
MVP		0.97
MPC		1.4
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.79
gMVP		0.97

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: rs878853113; hg19: chr17-15142862;