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]
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  • 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.614C>T (p.Pro205Leu)

CA271909

158987 (ClinVar)

Gene: MTM1
Condition: centronuclear myopathy
Inheritance Mode: X-linked inheritance (recessive (HP:0001419))
Link to MONDO
UUID: 63ca0364-f7f7-4ed4-8127-18f4feff245f
Approved on: 2024-08-07
Published on: 2024-10-01

HGVS expressions

NM_000252.3:c.614C>T
NM_000252.3(MTM1):c.614C>T (p.Pro205Leu)
NC_000023.11:g.150641354C>T
CM000685.2:g.150641354C>T
NC_000023.10:g.149809827C>T
CM000685.1:g.149809827C>T
NC_000023.9:g.149560485C>T
NG_008199.1:g.77781C>T
ENST00000684910.1:c.*147C>T
ENST00000685439.1:c.269C>T
ENST00000685944.1:c.614C>T
ENST00000686212.1:n.216C>T
ENST00000687215.1:c.*369C>T
ENST00000688152.1:c.*58C>T
ENST00000688403.1:c.-131C>T
ENST00000689314.1:c.659C>T
ENST00000689694.1:c.614C>T
ENST00000689810.1:c.*263C>T
ENST00000690282.1:c.-131C>T
ENST00000690351.1:c.*266C>T
ENST00000691232.1:c.269C>T
ENST00000691482.1:n.1629C>T
ENST00000691686.1:c.614C>T
ENST00000691851.1:c.614C>T
ENST00000692015.1:c.401C>T
ENST00000692638.1:c.*419C>T
ENST00000692852.1:c.614C>T
ENST00000692915.1:c.*821C>T
ENST00000370396.7:c.614C>T
ENST00000306167.11:n.481C>T
ENST00000370396.6:c.614C>T
ENST00000490530.1:n.553C>T
NM_000252.2:c.614C>T
NM_001376906.1:c.614C>T
NM_001376907.1:c.503C>T
NM_001376908.1:c.614C>T

Pathogenic

Met criteria codes 5
PS3_Moderate PM6 PM2_Supporting PS4 PP3
Not Met criteria codes 4
BA1 PM1 BS1 BP4

Evidence Links 0

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.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)
Met criteria codes
PS3_Moderate
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 impacts protein function (PS3_supporting; PMID: 10900271). Upgraded to moderate because the assay is specific and robust.
PM6
One patient from Austria was a suspected de novo case. The patient presented with severe myotubular myopathy.
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Coverage of the gene in the region in which this variant is found is adequate.
PS4
This variant has been reported in at least ten individuals from ten families with x-linked centro-nuclear myopathy (PS4; PMIDs: 28685322, 11793470, 8640223, 15725586, 10063835).
PP3
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 is also predicted to be damaging by several in-silico predictors.
Not Met criteria codes
BA1
This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Coverage of the gene in the region in which this variant is found is adequate.
PM1
I would propose that the region in which this variant is found be considered a hot spot point as it is associated with a CpG dinucleotide, considered a frequent hot spot location. Also, in ClinVar, lots of variants in this region are noted to be pathogenic (at residues 189-205, including Asn189Ser, Tyr192Cys, Leu194Pro, Thr197Ile, Tyr198His, Tyr198Ser, and Val204Gly).
BS1
This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Coverage of the gene in the region in which this variant is found is adequate.
BP4
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 is also predicted to be damaging by several in-silico predictors.
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