NM_000252.3(MTM1):c.575A>G (p.Tyr192Cys) AND Severe X-linked myotubular myopathy

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Oct 3, 2021
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:: RCV000146463.16

Allele description [Variation Report for NM_000252.3(MTM1):c.575A>G (p.Tyr192Cys)]

NM_000252.3(MTM1):c.575A>G (p.Tyr192Cys)

Gene:

MTM1:myotubularin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_000252.3(MTM1):c.575A>G (p.Tyr192Cys)

Other names:

NM_000252.3(MTM1):c.575A>G; p.Tyr192Cys

HGVS:

NC_000023.11:g.150641315A>G
NG_008199.1:g.77742A>G
NM_000252.3:c.575A>GMANE SELECT
NM_001376906.1:c.575A>G
NM_001376907.1:c.464A>G
NM_001376908.1:c.575A>G
NP_000243.1:p.Tyr192Cys
NP_000243.1:p.Tyr192Cys
NP_001363835.1:p.Tyr192Cys
NP_001363836.1:p.Tyr155Cys
NP_001363837.1:p.Tyr192Cys
LRG_839t1:c.575A>G
LRG_839:g.77742A>G
LRG_839p1:p.Tyr192Cys
NC_000023.10:g.149809788A>G
NM_000252.2:c.575A>G

Protein change:

Y155C

Links:

dbSNP: rs587783838

NCBI 1000 Genomes Browser:

rs587783838

Molecular consequence:

NM_000252.3:c.575A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376906.1:c.575A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376907.1:c.464A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376908.1:c.575A>G - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000193751	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 10, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000634492	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 3, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20434914, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000193751

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 10, 2015)

germline

clinical testing

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

SCV000634492

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 3, 2021)

germline

clinical testing

PubMed (2)
[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
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Novel molecular diagnostic approaches for X-linked centronuclear (myotubular) myopathy reveal intronic mutations.

Tosch V, Vasli N, Kretz C, Nicot AS, Gasnier C, Dondaine N, Oriot D, Barth M, Puissant H, Romero NB, Bönnemann CG, Heller B, Duval G, Biancalana V, Laporte J.

Neuromuscul Disord. 2010 Jun;20(6):375-81. doi: 10.1016/j.nmd.2010.03.015.

PubMed [citation]

PMID:: 20434914

See all PubMed Citations (3)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000193751.2

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000634492.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects MTM1 function (PMID: 20434914). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 158984). This missense change has been observed in individuals with myotubular myopathy (PMID: 20434914; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with cysteine at codon 192 of the MTM1 protein (p.Tyr192Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. 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.

#	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: Oct 20, 2024

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