NM_001267550.2(TTN):c.835C>T (p.Arg279Trp) AND Myopathy, myofibrillar, 9, with early respiratory failure

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 27, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000013495.32

Allele description [Variation Report for NM_001267550.2(TTN):c.835C>T (p.Arg279Trp)]

NM_001267550.2(TTN):c.835C>T (p.Arg279Trp)

Gene:

TTN:titin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.835C>T (p.Arg279Trp)

Other names:

p.R279W:CGG>TGG

HGVS:

NC_000002.12:g.178799566G>A
NG_011618.3:g.36237C>T
NM_001256850.1:c.835C>T
NM_001267550.2:c.835C>TMANE SELECT
NM_003319.4:c.835C>T
NM_133378.4:c.835C>T
NM_133379.5:c.835C>T
NM_133432.3:c.835C>T
NM_133437.4:c.835C>T
NP_001243779.1:p.Arg279Trp
NP_001254479.2:p.Arg279Trp
NP_003310.4:p.Arg279Trp
NP_596869.4:p.Arg279Trp
NP_596870.2:p.Arg279Trp
NP_597676.3:p.Arg279Trp
NP_597681.4:p.Arg279Trp
LRG_391t1:c.835C>T
LRG_391:g.36237C>T
NC_000002.11:g.179664293G>A
NM_001267550.1:c.835C>T
Q8WZ42:p.Arg279Trp

Protein change:

R279W; ARG279TRP

Links:

UniProtKB: Q8WZ42#VAR_026634; OMIM: 188840.0011; dbSNP: rs138060032

NCBI 1000 Genomes Browser:

rs138060032

Molecular consequence:

NM_001256850.1:c.835C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.835C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.835C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.835C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133379.5:c.835C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.835C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.835C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Myopathy, myofibrillar, 9, with early respiratory failure (MFM9)
Synonyms:: EDSTROM MYOPATHY; MYOPATHY, PROXIMAL, WITH EARLY RESPIRATORY MUSCLE INVOLVEMENT; Hereditary myopathy with early respiratory failure; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011362; MedGen: C1863599; Orphanet: 178464; Orphanet: 34521; OMIM: 603689

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MIR6724-3 microRNA 6724-3 [Homo sapiens]
MIR6724-3 microRNA 6724-3 [Homo sapiens]
Gene ID:103504739

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000033742	OMIM	no assertion criteria provided	Pathogenic (Jun 10, 2005)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 10053013, 15802564
SCV001294158	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24271327, 15802564 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000033742

OMIM

no assertion criteria provided

Pathogenic
(Jun 10, 2005)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV001294158

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Autosomal dominant myopathy with proximal weakness and early respiratory muscle involvement maps to chromosome 2q.

Nicolao P, Xiang F, Gunnarsson LG, Giometto B, Edström L, Anvret M, Zhang Z.

Am J Hum Genet. 1999 Mar;64(3):788-92.

PubMed [citation]

PMID:: 10053013
PMCID:: PMC1377796

Reply: Hereditary myopathy with early respiratory failure is caused by mutations in the titin FN3 119 domain.

Pfeffer G, Griffin H, Pyle A, Horvath R, Chinnery PF.

Brain. 2014 Apr;137(Pt 4):e271. doi: 10.1093/brain/awt306. Epub 2013 Nov 21. No abstract available.

PubMed [citation]

PMID:: 24271327
PMCID:: PMC3959549

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000033742.3

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

Description

In 2 large unrelated Swedish families described by Nicolao et al. (1999) segregating autosomal dominant myofibrillar myopathy-9 with early respiratory failure (MFM9; 603689), Lange et al. (2005) identified a C-to-T transition in the TTN gene resulting in an arg-to-trp substitution at codon 279 (R279W) in the alpha-R1 region of the protein kinase regulatory tail of titin. This mutation showed complete segregation with the disease in the 2 families. The mutation was not reported in single-nucleotide polymorphism (SNP) databases and was not found in 200 normal Swedish controls. An additional Swedish patient with an identical phenotype but without known genealogic relation to anyone in the 2 original families was found to have the same mutation on the same haplotype, indicating a common ancestry. The R279W mutant protein kinase domain (TK) showed no difference in calmodulin (114180)-stimulated catalytic activity when compared with wildtype TK. However, the interaction of TK with NBR1 (166945) was dramatically reduced. In patient biopsies, NBR1 was localized abnormally diffusely in diseased muscle instead of being M band- and Z disc-associated, although in HMERF 50% of TK was expected to be wildtype. This suggested a dominant-negative mechanism of action for this mutation.

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

From Illumina Laboratory Services, Illumina, SCV001294158.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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: May 12, 2024

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