Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000252.3(MTM1):c.205C>T (p.Arg69Cys)

CA255665

11055 (ClinVar)

Gene: MTM1
Condition: centronuclear myopathy
Inheritance Mode: X-linked inheritance (recessive (HP:0001419))
Link to MONDO
UUID: be301769-94ba-4548-a115-923b0015cdc9
Approved on: 2024-08-07
Published on: 2024-10-01

HGVS expressions

NM_000252.3:c.205C>T
NM_000252.3(MTM1):c.205C>T (p.Arg69Cys)
NC_000023.11:g.150598660C>T
CM000685.2:g.150598660C>T
NC_000023.10:g.149767124C>T
CM000685.1:g.149767124C>T
NC_000023.9:g.149517782C>T
NG_008199.1:g.35078C>T
ENST00000684910.1:c.136+2090C>T
ENST00000685439.1:c.-3-20378C>T
ENST00000685944.1:c.205C>T
ENST00000687215.1:c.-81C>T
ENST00000687365.1:n.260C>T
ENST00000688152.1:c.205C>T
ENST00000688403.1:c.-301+29798C>T
ENST00000689314.1:c.205C>T
ENST00000689694.1:c.205C>T
ENST00000689810.1:c.205C>T
ENST00000690282.1:c.-301+29942C>T
ENST00000690351.1:c.136+2090C>T
ENST00000691232.1:c.-3-20378C>T
ENST00000691686.1:c.205C>T
ENST00000691851.1:c.205C>T
ENST00000692015.1:c.205C>T
ENST00000692638.1:c.136+2090C>T
ENST00000692852.1:c.205C>T
ENST00000692915.1:c.205C>T
ENST00000693422.1:n.266C>T
ENST00000370396.7:c.205C>T
ENST00000306167.11:n.244C>T
ENST00000370396.6:c.205C>T
ENST00000424519.1:c.205C>T
ENST00000490530.1:n.170+2090C>T
NM_000252.2:c.205C>T
NM_001376906.1:c.205C>T
NM_001376907.1:c.205C>T
NM_001376908.1:c.205C>T
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Pathogenic

Met criteria codes 5
PP1_Strong PS3 PP3 PM2_Supporting PS4_Moderate
Not Met criteria codes 4
BA1 BS1 BP4 PM5

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MTM1 Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Congenital Myopathies VCEP
The c.205C>T (NM_000252.3(MTM1):c.205C>T (p.Arg69Cys)) variant in MTM1 is a missense variant predicted to cause substitution of Arg by Cys at amino acid 69. The variant was found in at least 3 probands from three families with X-linked centronuclear myopathy (PS4_Moderate; PMIDs: 9285787, 15811014). The variant has been reported to segregate with X-linked centronuclear myopathy in 6 affected individuals from one family (PP1_strong; PMID: 15811014). The variant specific model in mice showed muscle weakness and low myotubularin protein concentrations, indicating that this variant impacts protein function (PS3; PMID: 22068590; Pierson et al., 2012). The computational predictor REVEL gives a score of 0.825, which is above the threshold of 0.7, set by the Congenital Myopathies VCEP, evidence that correlates with impact to MTM1 function (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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_Moderate, PP1_Strong, PS3, PP3, PM2_Supporting; Version 1, 8/7/2024).
Met criteria codes
PP1_Strong
The variant has been reported to segregate with X-linked centronuclear myopathy in 6 affected individuals from one family (PP1_strong; PMID: 15811014).
PS3
The variant specific model in mice showed muscle weakness and low myotubularin protein concentrations, indicating that this variant impacts protein function (PMID: 22068590; Pierson et al., 2012).
This was a mouse model. Hemizygous male mice with the Arg69Cys mutant acquire early muscle atrophy before weakness at 2 months. The average survival time is 66 weeks. Histopathological analysis rrevealed small myofibers with centrally located nuclei. Myotublarin protein is very low because the nucleotide change results in skipping of exon 4 in most mRNAs, causing early termination of myotubularin translation at exon 5. Some full-length Mtm mRNA with the mutation are available, which allows for sufficient myotubularin function to match the fairly mild phenotypic presentation. The mutant mice were made with PCR mutagenesis to trigger the mutation and the DNA was subcloned into the targeting vector. The wild-type sequence was replaced with a vector. A human quadricep sample from a patient with this mutation indicated that the mutation results in the skipping of exon 4 and early truncation of the protein in humans as well. PubMed:22068590
PP3
The computational predictor REVEL gives a score of 0.825, which is above the threshold of 0.7, set by the Congenital Myopathies VCEP, evidence that correlates with impact to MTM1 function (PP3).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Coverage of the region of the gene in which the variant was found is adequate.
PS4_Moderate
Variant was found in three probands with X-linked centronuclear myopathy (PMID: 9285787, 15811014).
Not Met criteria codes
BA1
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
BS1
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
BP4
The computational predictor REVEL gives a score of 0.825, which is above the threshold of 0.7, set by the Congenital Myopathies VCEP, evidence that correlates with impact to MTM1 function (PP3).
PM5
There are two other variants in ClinVar at this same residue, Arg to Gly and Arg to Cys, but the former is classified as a variant of uncertain significance for X-linked centronuclear myopathy, and the later is classified as pathogenic for the condition (but by only one submitter, back in 2013, with no evidence).
Curation History
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