NM_000530.8(MPZ):c.448+1G>A AND Charcot-Marie-Tooth disease, type I

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 23, 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:: RCV003581906.1

Allele description

NM_000530.8(MPZ):c.448+1G>A

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.448+1G>A

HGVS:

NC_000001.11:g.161306707C>T
NG_008055.1:g.8266G>A
NM_000530.6:c.448+1G>A
NM_000530.8:c.448+1G>AMANE SELECT
NM_001315491.2:c.448+1G>A
LRG_256t1:c.448+1G>A
LRG_256:g.8266G>A
NC_000001.10:g.161276497C>T

Molecular consequence:

NM_000530.8:c.448+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001315491.2:c.448+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Charcot-Marie-Tooth disease, type I (CMT1)
Synonyms:: Charcot-Marie-Tooth Neuropathy Type 1; Hereditary Motor and Sensory Neuropathy 1; Charcot-Marie-Tooth, Type 1
Identifiers:: MONDO: MONDO:0019011; MedGen: C0751036

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004292954	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 23, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25614874, 16199547, 14711881, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004292954

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 23, 2023)

germline

clinical testing

PubMed (4)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy.

DiVincenzo C, Elzinga CD, Medeiros AC, Karbassi I, Jones JR, Evans MC, Braastad CD, Bishop CM, Jaremko M, Wang Z, Liaquat K, Hoffman CA, York MD, Batish SD, Lupski JR, Higgins JJ.

Mol Genet Genomic Med. 2014 Nov;2(6):522-9. doi: 10.1002/mgg3.106. Epub 2014 Aug 21.

PubMed [citation]

PMID:: 25614874
PMCID:: PMC4303222

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV004292954.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 2504290). Disruption of this splice site has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 25614874). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 3 of the MPZ gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MPZ are known to be pathogenic (PMID: 14711881).

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

Last Updated: May 7, 2024

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Relating variation to medicine