NM_000530.8(MPZ):c.645G>A (p.Gln215=) AND Charcot-Marie-Tooth disease

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 7, 2024
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:: RCV003994259.1

Allele description [Variation Report for NM_000530.8(MPZ):c.645G>A (p.Gln215=)]

NM_000530.8(MPZ):c.645G>A (p.Gln215=)

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.645G>A (p.Gln215=)

HGVS:

NC_000001.11:g.161306108C>T
NG_008055.1:g.8865G>A
NM_000530.8:c.645G>AMANE SELECT
NM_001315491.2:c.645G>A
NP_000521.2:p.Gln215=
NP_001302420.1:p.Gln215=
LRG_256:g.8865G>A
NC_000001.10:g.161275898C>T

Links:

dbSNP: rs1670232790

NCBI 1000 Genomes Browser:

rs1670232790

Molecular consequence:

NM_000530.8:c.645G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001315491.2:c.645G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Name:: Charcot-Marie-Tooth disease
Synonyms:: Charcot-Marie-Tooth Neuropathy
Identifiers:: MONDO: MONDO:0015626; MedGen: C0007959; OMIM: PS118220

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004812593	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 7, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7530550, 9588852, 14711881, 16252242, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004812593

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 7, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of a de novo insertional mutation in P0 in a patient with a Déjérine-Sottas syndrome (DSS) phenotype.

Rautenstrauss B, Nelis E, Grehl H, Pfeiffer RA, Van Broeckhoven C.

Hum Mol Genet. 1994 Sep;3(9):1701-2. No abstract available.

PubMed [citation]

PMID:: 7530550

A small direct tandem duplication of the myelin protein zero gene in a patient with Dejerine-Sottas disease phenotype.

Tachi N, Kozuka N, Ohya K, Chiba S, Yamashita S.

J Neurol Sci. 1998 Apr 1;156(2):167-71.

PubMed [citation]

PMID:: 9588852

See all PubMed Citations (5)

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV004812593.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change is a synonymous (silent) substitution in the last nucleotide of exon 5 (of 6) of MPZ that is predicted to impact splicing (SpliceAI). RNA studies in patient cells demonstrate near complete aberrant splicing from the variant allele, demonstrating exon 5 skipping (p.Ser195Argfs*37) and intron 5 retention (p.Thr216Valfs*22) (RNA4RD). While loss of function is not an established mechanism of disease the impact of the aberrant transcripts is consistent with previously reported pathogenic truncating variants in the gene that escape nonsense-mediated decay (PMID: 7530550, 9588852, 14711881, 16252242). This variant is absent from the population database gnomAD v4.0. This variant has been detected in at least two individuals with demyelinating neuropathy (Melbourne Health Pathology; Invitae personal communication). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PM2_Supporting, PS4_Supporting.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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