rs104894620

Variant names:

• chr17-15239584-A-C
• rs104894620
• ENST00000494511.7:c.2T>G

Your query was ambiguous. Multiple possible variants found:

• chr17-15239584-A-C
• chr17-15239584-A-G
• chr17-15239584-A-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The ENST00000494511.7(PMP22):​c.2T>G​(p.Met1?) variant causes a start lost 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMP22 ENST00000494511.7 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.16
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 1A

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Ambry Genetics
• hereditary neuropathy with liability to pressure palsies

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• Charcot-Marie-Tooth disease type 1E

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 34 pathogenic variants. Next in-frame start position is after 43 codons. Genomic position: 15231069. Lost 0.455 part of the original CDS.
• PS1: Another start lost variant in ENST00000494511.7 (PMP22) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-15239584-A-C is Pathogenic according to our data. Variant chr17-15239584-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 637834.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMP22	NM_000304.4	c.206T>G	p.Met69Arg	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.206T>G	p.Met69Arg	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: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Sep 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 69 of the PMP22 protein (p.Met69Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 21194947, 34255403). ClinVar contains an entry for this variant (Variation ID: 637834). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PMP22 protein function with a positive predictive value of 95%. This variant disrupts the p.Met69 amino acid residue in PMP22. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8275092, 26102530). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Charcot-Marie-Tooth disease Uncertain:1

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.98	D;D;D;D;D;.;.;D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;.;.;.;.;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.3	M;M;M;.;.;.;.;.;.
PhyloP100		9.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.4	.;D;D;.;D;.;.;.;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	.;D;D;.;D;.;.;.;D
Sift4G	Uncertain	0.0030	D;D;D;.;D;.;.;.;D
Polyphen		1.0	D;D;D;.;.;.;.;.;.
Vest4		0.98
MutPred		0.91		Gain of catalytic residue at M69 (P = 0.044);Gain of catalytic residue at M69 (P = 0.044);Gain of catalytic residue at M69 (P = 0.044);Gain of catalytic residue at M69 (P = 0.044);Gain of catalytic residue at M69 (P = 0.044);.;.;Gain of catalytic residue at M69 (P = 0.044);Gain of catalytic residue at M69 (P = 0.044);
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.94
gMVP		0.99
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs104894620; hg19: chr17-15142901;