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NM_000530.8(MPZ):c.112G>T (p.Val38Phe) AND Charcot-Marie-Tooth disease dominant intermediate D

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Mar 30, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002221381.2

Allele description [Variation Report for NM_000530.8(MPZ):c.112G>T (p.Val38Phe)]

NM_000530.8(MPZ):c.112G>T (p.Val38Phe)

Gene:
MPZ:myelin protein zero [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q23.3
Genomic location:
Preferred name:
NM_000530.8(MPZ):c.112G>T (p.Val38Phe)
HGVS:
  • NC_000001.11:g.161307380C>A
  • NG_008055.1:g.7593G>T
  • NM_000530.8:c.112G>TMANE SELECT
  • NM_001315491.2:c.112G>T
  • NP_000521.2:p.Val38Phe
  • NP_001302420.1:p.Val38Phe
  • LRG_256t1:c.112G>T
  • LRG_256:g.7593G>T
  • NC_000001.10:g.161277170C>A
  • NM_000530.6:c.112G>T
Protein change:
V38F
Links:
dbSNP: rs2102260135
NCBI 1000 Genomes Browser:
rs2102260135
Molecular consequence:
  • NM_000530.8:c.112G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001315491.2:c.112G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Charcot-Marie-Tooth disease dominant intermediate D
Synonyms:
CHARCOT-MARIE-TOOTH NEUROPATHY, DOMINANT INTERMEDIATE D; Charcot-Marie-Tooth disease dominant intermediate 3; CMT DI3
Identifiers:
MONDO: MONDO:0011909; MedGen: C1843075; OMIM: 607791

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002498600Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Mar 30, 2023) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV002498600.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change in MPZ is predicted to replace valine with phenylalanine at codon 38, p.(Val38Phe). The valine residue is highly conserved (100 vertebrates, UCSC), and is located in the Ig-like V-type domain in a Charcot-Marie-Tooth disease mutational hotspot, amino acids 35-39 (ClinVar). There is a small physicochemical difference between valine and phenylalanine. This variant is absent from gnomAD v2.1 and v3.1. To our knowledge, this variant has not been reported in the literature in any individuals with neuropathy. Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). Another missense variant c.113T>A, p.Val38Asp in the same codon with a larger physicochemical difference has been classified as likely pathogenic for Charcot-Marie-Tooth disease (ClinVar Variation ID: 860059). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM1, PM2_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 20, 2024