VCV000599406.10 - ClinVar

NM_002677.5(PMP2):c.155T>C (p.Ile52Thr)

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.

(7)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002677.5(PMP2):c.155T>C (p.Ile52Thr)

Variation ID: 599406 Accession: VCV000599406.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q21.13 8: 81444908 (GRCh38) [ NCBI UCSC ] 8: 82357143 (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	Jan 22, 2019	May 1, 2024	Nov 19, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002677.5:c.155T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002668.1:p.Ile52Thr	missense
NM_001348381.2:c.74-307T>C		intron variant
NC_000008.11:g.81444908A>G
NC_000008.10:g.82357143A>G
NG_052979.1:g.7616T>C

... more HGVS ... less HGVS

Protein change

I52T

Other names

Canonical SPDI

NC_000008.11:81444907: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

OMIM: 170715.0002 dbSNP: rs1563518388 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.
PMP2		-	-	GRCh38 GRCh37	106	151

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, demyelinating, type 1G	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jul 15, 2022	RCV000736031.7
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Jul 21, 2021	RCV001267025.5
not provided	Pathogenic (1)	criteria provided, single submitter	Nov 19, 2023	RCV002535440.3

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.
Likely pathogenic (Nov 01, 2018)	criteria provided, single submitter (Punetha et al. (Mol Genet Metab. 2018)) Method: research	Charcot-Marie-Tooth disease, demyelinating, type 1G (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine Accession: SCV000920876.1 First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019	Publications: PubMed (1) PubMed: 30249361 Comment: We found a PMP2 variant c.155Tâ€¯>â€¯C, p.(Ile52Thr) that segregates with the disease in 4 affected individuals of a multi-generational family. Clinical Features: Peripheral neuropathy (present) Sex: female Geographic origin: United States
Likely pathogenic (Feb 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease, demyelinating, type 1G Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001548531.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Publications: PubMed (7) PubMed: 26257172‚ 27009151‚ 28747762‚ 30249361‚ 30941082‚ 31412900‚ 32277537 Comment: This PMP2 variant has been identified in multiple multi-generation families segregating autosomal dominant Charcot-Marie-Tooth disease including one instance where it was reported to be a … (more) This PMP2 variant has been identified in multiple multi-generation families segregating autosomal dominant Charcot-Marie-Tooth disease including one instance where it was reported to be a de novo change in an affected individual. c.155T>C is absent from a large population database. This variant has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, however these algorithms are optimized for loss of function variants. The isoleucine residue at this position is conserved across most species assessed and there is functional evidence that this substitution may result in decreased myelin stability and altered protein dynamics. We consider c.155T>C to be likely pathogenic. (less)
Pathogenic (Jul 19, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease, demyelinating, type 1G Affected status: yes Allele origin: de novo	Centogene AG - the Rare Disease Company Accession: SCV002059495.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Likely pathogenic (Jul 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease, demyelinating, type 1G Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581030.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PM6_STR, PM1_SUP, PM2_SUP, PP1	Number of individuals with the variant: 1 Sex: female
Pathogenic (Nov 19, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003440895.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 27009151‚ 30249361‚ 28747762 Comment: This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 52 of the PMP2 protein (p.Ile52Thr). … (more) This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 52 of the PMP2 protein (p.Ile52Thr). 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: 27009151, 30249361). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 599406). 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. Experimental studies have shown that this missense change affects PMP2 function (PMID: 28747762). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Jul 21, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001445206.4 First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 26828946‚ 27009151‚ 28747762‚ 30249361 Comment: The c.155T>C (p.I52T) alteration is located in coding exon 2 of the PMP2 gene. This alteration results from a T to C substitution at nucleotide … (more) The c.155T>C (p.I52T) alteration is located in coding exon 2 of the PMP2 gene. This alteration results from a T to C substitution at nucleotide position 155, causing the isoleucine (I) at amino acid position 52 to be replaced by a threonine (T). Based on data from the Genome Aggregation Database (gnomAD), the PMP2 c.155T>C alteration was not observed, with coverage at this position. This alteration has been detected in multiple individuals with Charcot-Marie-Tooth (CMT) disease type 1 and has been found to co-segregate with disease in different families (Motley, 2016; Punetha, 2018). The p.I52 amino acid is located in the highly-conserved ligand-binding core domain of PMP2 (Hong, 2016; Motley, 2016). Functional analysis showed the p.I52T alteration affects protein aggregation tendency and dynamics (Ruskamo, 2017). The p.I52T alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
Pathogenic (Jan 16, 2019)	no assertion criteria provided Method: literature only	CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1G Affected status: not provided Allele origin: germline	OMIM Accession: SCV000864250.1 First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019	Publications: PubMed (2) PubMed: 27009151‚ 30249361 Comment on evidence: In a father and son (family 1) with demyelinating Charcot-Marie-Tooth disease, type 1G (CMT1G; 618279), Motley et al. (2016) identified a heterozygous c.155T-C transition in … (more) In a father and son (family 1) with demyelinating Charcot-Marie-Tooth disease, type 1G (CMT1G; 618279), Motley et al. (2016) identified a heterozygous c.155T-C transition in the PMP2 gene, resulting in an ile52-to-thr (I52T) substitution at a conserved residue in the beta barrel of PMP2. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, occurred de novo in the father. The variant was not found in the Exome Variant Server, 1000 Genomes Project, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed, but Motley et al. (2016) suggested that the mutation may result in aberrant transport of fatty acids and possibly result in a toxic gain of function. Punetha et al. (2018) reported another family with CMT1G due to a heterozygous I52T mutation in the PMP2 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. (less)

Comment:

This PMP2 variant has been identified in multiple multi-generation families segregating autosomal dominant Charcot-Marie-Tooth disease including one instance where it was reported to be a de novo change in an affected individual. c.155T>C is absent from a large population database. This variant has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, however these algorithms are optimized for loss of function variants. The isoleucine residue at this position is conserved across most species assessed and there is functional evidence that this substitution may result in decreased myelin stability and altered protein dynamics. We consider c.155T>C to be likely pathogenic.

Comment:

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 52 of the PMP2 protein (p.Ile52Thr). 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: 27009151, 30249361). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 599406). 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. Experimental studies have shown that this missense change affects PMP2 function (PMID: 28747762). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.155T>C (p.I52T) alteration is located in coding exon 2 of the PMP2 gene. This alteration results from a T to C substitution at nucleotide position 155, causing the isoleucine (I) at amino acid position 52 to be replaced by a threonine (T). Based on data from the Genome Aggregation Database (gnomAD), the PMP2 c.155T>C alteration was not observed, with coverage at this position. This alteration has been detected in multiple individuals with Charcot-Marie-Tooth (CMT) disease type 1 and has been found to co-segregate with disease in different families (Motley, 2016; Punetha, 2018). The p.I52 amino acid is located in the highly-conserved ligand-binding core domain of PMP2 (Hong, 2016; Motley, 2016). Functional analysis showed the p.I52T alteration affects protein aggregation tendency and dynamics (Ruskamo, 2017). The p.I52T alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

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
Early onset demyelinating Charcot-Marie-Tooth disease caused by a novel in-frame isoleucine deletion in peripheral myelin protein 2.	Geroldi A	Journal of the peripheral nervous system : JPNS	2020	PMID: 32277537
Peripheral myelin protein 2 - a novel cluster of mutations causing Charcot-Marie-Tooth neuropathy.	Palaima P	Orphanet journal of rare diseases	2019	PMID: 31412900
Peripheral Demyelinating Diseases: From Biology to Translational Medicine.	Kamil K	Frontiers in neurology	2019	PMID: 30941082
Identification of a pathogenic PMP2 variant in a multi-generational family with CMT type 1: Clinical gene panels versus genome-wide approaches to molecular diagnosis.	Punetha J	Molecular genetics and metabolism	2018	PMID: 30249361
Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2.	Ruskamo S	Scientific reports	2017	PMID: 28747762
De novo PMP2 mutations in families with type 1 Charcot-Marie-Tooth disease.	Motley WW	Brain : a journal of neurology	2016	PMID: 27009151
A Mutation in PMP2 Causes Dominant Demyelinating Charcot-Marie-Tooth Neuropathy.	Hong YB	PLoS genetics	2016	PMID: 26828946
Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy.	Gonzaga-Jauregui C	Cell reports	2015	PMID: 26257172

Text-mined citations for rs1563518388 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_002677.5(PMP2):c.155T>C (p.Ile52Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1563518388 ...