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NM_000252.3(MTM1):c.614C>T (p.Pro205Leu) AND Severe X-linked myotubular myopathy

Germline classification:
Pathogenic (3 submissions)
Last evaluated:
Dec 8, 2022
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000146466.14

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)
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:
Severe X-linked myotubular myopathy (CNMX)
Synonyms:
X-linked centronuclear myopathy; MYOTUBULAR MYOPATHY 1; Myotubular myopathy, X-linked
Identifiers:
MONDO: MONDO:0010683; MedGen: C0410203; Orphanet: 596; OMIM: 310400

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000193754Genetic Services Laboratory, University of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2007)
Pathogenic
(Feb 8, 2013)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001445916Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(May 19, 2019)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002242511Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Dec 8, 2022)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee..

Genet Med. 2008 Apr;10(4):294-300. doi: 10.1097/GIM.0b013e31816b5cae.

PubMed [citation]
PMID:
18414213

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753
See all PubMed Citations (7)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000193754.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001445916.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant has been previously reported as a hemizygous change in males and as a heterozygous change in affected female carriers with X-linked myotubular myopathy (PMID: 8640223, 11793470, 28685322, 30047259). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.614C>T (p.Pro205Leu) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.614C>T (p.Pro205Leu) variant is classified as Pathogenic.

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

From Invitae, SCV002242511.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Experimental studies have shown that this missense change affects MTM1 function (PMID: 10900271). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MTM1 protein function. ClinVar contains an entry for this variant (Variation ID: 158987). This variant is also known as C668T (P223L). This missense change has been observed in individual(s) with myotubular myopathy (PMID: 8640223, 11793470, 28685322). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 205 of the MTM1 protein (p.Pro205Leu). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Mar 16, 2024