NM_000252.3(MTM1):c.1184G>A (p.Ser395Asn) AND Severe X-linked myotubular myopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 3, 2023
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:: RCV001051781.7

Allele description [Variation Report for NM_000252.3(MTM1):c.1184G>A (p.Ser395Asn)]

NM_000252.3(MTM1):c.1184G>A (p.Ser395Asn)

Gene:

MTM1:myotubularin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_000252.3(MTM1):c.1184G>A (p.Ser395Asn)

HGVS:

NC_000023.11:g.150657951G>A
NG_008199.1:g.94378G>A
NM_000252.3:c.1184G>AMANE SELECT
NM_001376906.1:c.1184G>A
NM_001376907.1:c.1073G>A
NM_001376908.1:c.1184G>A
NP_000243.1:p.Ser395Asn
NP_001363835.1:p.Ser395Asn
NP_001363836.1:p.Ser358Asn
NP_001363837.1:p.Ser395Asn
LRG_839t1:c.1184G>A
LRG_839:g.94378G>A
NC_000023.10:g.149826424G>A
NM_000252.2:c.1184G>A

Protein change:

S358N

Links:

dbSNP: rs2040151430

NCBI 1000 Genomes Browser:

rs2040151430

Molecular consequence:

NM_000252.3:c.1184G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376906.1:c.1184G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376907.1:c.1073G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376908.1:c.1184G>A - 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
SCV001215959	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 12, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004563377	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Nov 3, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001215959

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 12, 2019)

germline

clinical testing

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

SCV004563377

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Uncertain significance
(Nov 3, 2023)

germline

clinical testing

Citation Link

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001215959.5

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

Description

This variant has not been reported in the literature in individuals with MTM1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 395 of the MTM1 protein (p.Ser395Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine.

#	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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004563377.1

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

#	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: Feb 28, 2024

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