VCV002444073.2 - ClinVar

NM_000304.4(PMP22):c.124T>C (p.Cys42Arg)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000304.4(PMP22):c.124T>C (p.Cys42Arg)

Variation ID: 2444073 Accession: VCV002444073.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p12 17: 15259148 (GRCh38) [ NCBI UCSC ] 17: 15162465 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 18, 2023	Feb 14, 2024	May 6, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000304.4:c.124T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000295.1:p.Cys42Arg	missense
NM_001281455.2:c.124T>C	NP_001268384.1:p.Cys42Arg	missense
NM_001281456.2:c.124T>C	NP_001268385.1:p.Cys42Arg	missense
NM_001330143.2:c.124T>C	NP_001317072.1:p.Cys42Arg	missense
NM_153321.3:c.124T>C	NP_696996.1:p.Cys42Arg	missense
NM_153322.3:c.124T>C	NP_696997.1:p.Cys42Arg	missense
NR_104017.2:n.219T>C		non-coding transcript variant
NC_000017.11:g.15259148A>G
NC_000017.10:g.15162465A>G
NG_007949.1:g.11180T>C
LRG_263:g.11180T>C
LRG_263t1:c.124T>C	LRG_263p1:p.Cys42Arg

... more HGVS ... less HGVS

Protein change

C42R

Other names

Canonical SPDI

NC_000017.11:15259147:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PMP22		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	408	526

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Charcot-Marie-Tooth disease, type IA	Uncertain significance (1)	criteria provided, single submitter	Feb 23, 2023	RCV003152871.1
Charcot-Marie-Tooth disease, type I	Uncertain significance (1)	criteria provided, single submitter	May 6, 2023	RCV003581894.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease, type IA Affected status: yes Allele origin: unknown	3billion Accession: SCV003841350.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 27549087 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product … (more) The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PMP22 related disorder (PMID: 27549087). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Distal muscle weakness (present) , Somatic sensory dysfunction (present) , Abnormal foot morphology (present)
Uncertain significance (May 06, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease, type I Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004296754.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 27549087‚ 29127354 Comment: 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 … (more) 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. 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. ClinVar contains an entry for this variant (Variation ID: 2444073). This missense change has been observed in individual(s) with hereditary neuropathy with liability to pressure palsies and/or PMP22-related conditions (PMID: 27549087, 29127354). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 42 of the PMP22 protein (p.Cys42Arg). (less)

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PMP22 related disorder (PMID: 27549087). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

Comment:

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. 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. ClinVar contains an entry for this variant (Variation ID: 2444073). This missense change has been observed in individual(s) with hereditary neuropathy with liability to pressure palsies and/or PMP22-related conditions (PMID: 27549087, 29127354). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 42 of the PMP22 protein (p.Cys42Arg).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical and Molecular Characterization of PMP22 point mutations in Taiwanese patients with Inherited Neuropathy.	Liao YC	Scientific reports	2017	PMID: 29127354
Improving diagnosis of inherited peripheral neuropathies through gene panel analysis.	Laššuthová P	Orphanet journal of rare diseases	2016	PMID: 27549087

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000304.4(PMP22):c.124T>C (p.Cys42Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...