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NM_000252.3(MTM1):c.614C>T (p.Pro205Leu) AND Centronuclear myopathy

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Aug 7, 2024
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV004732467.1

Allele description [Variation Report for NM_000252.3(MTM1):c.614C>T (p.Pro205Leu)]

NM_000252.3(MTM1):c.614C>T (p.Pro205Leu)

Gene:
MTM1:myotubularin 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Xq28
Genomic location:
Preferred name:
NM_000252.3(MTM1):c.614C>T (p.Pro205Leu)
Other names:
NM_000252.3(MTM1):c.614C>T
HGVS:
  • NC_000023.11:g.150641354C>T
  • NG_008199.1:g.77781C>T
  • NM_000252.3:c.614C>TMANE SELECT
  • NM_001376906.1:c.614C>T
  • NM_001376907.1:c.503C>T
  • NM_001376908.1:c.614C>T
  • NP_000243.1:p.Pro205Leu
  • NP_000243.1:p.Pro205Leu
  • NP_001363835.1:p.Pro205Leu
  • NP_001363836.1:p.Pro168Leu
  • NP_001363837.1:p.Pro205Leu
  • LRG_839t1:c.614C>T
  • LRG_839:g.77781C>T
  • LRG_839p1:p.Pro205Leu
  • NC_000023.10:g.149809827C>T
  • NM_000252.2:c.614C>T
  • Q13496:p.Pro205Leu
Protein change:
P168L
Links:
UniProtKB: Q13496#VAR_006393; dbSNP: rs587783841
NCBI 1000 Genomes Browser:
rs587783841
Molecular consequence:
  • NM_000252.3:c.614C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001376906.1:c.614C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001376907.1:c.503C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001376908.1:c.614C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Centronuclear myopathy (CNM)
Synonyms:
Myotubular myopathy; Centronuclear myopathy, congenital
Identifiers:
MONDO: MONDO:0018947; MedGen: C0175709; OMIM: PS160150

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005367899ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen CongenMyopathy ACMG Specifications MTM1 V1.0.0)		Pathogenic
(Aug 7, 2024) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen, SCV005367899.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.614C>T variant in MTM1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 205. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.968, which is above the Congenital Myopathies VCEP threshold of 0.7, evidence that correlates with impact to MTM1 function (PP3). This variant has been reported in at least ten individuals with centronuclear myopathy (PS4; PMIDs: 28685322, 11793470, 8640223, 15725586, 10063835). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in one individual with X-linked centronuclear myopathy. (PM6; PMID: 10063835). A phosphatase assay using recombinant human myotubularin as a fusion protein in E. coli, showed that the mutation dramatically reduced phosphatase activity, indicating that this variant may impact protein function (PS3_Moderate; PMID: 10900271). In summary, this variant meets the criteria to be classified as pathogenic for X-linked centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PM6, PS3_Moderate, PP3, PM2_Supporting. (Congenital Myopathies VCEP specifications version 1; 8/7/2024)

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

Last Updated: Feb 25, 2025