NM_001267550.2(TTN):c.835C>T (p.Arg279Trp) AND not specified

Germline classification:: Likely benign (2 submissions)
Last evaluated:: Jun 19, 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:: RCV000219791.7

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]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000272796	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Apr 9, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004021283	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jun 19, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 24558114, 27930701, 26516846, 24231549, 15802564, 24105469, 24578547, 20708934 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000272796

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely benign
(Apr 9, 2018)

germline

clinical testing

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

SCV004021283

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Jun 19, 2023)

germline

clinical testing

PubMed (8)
[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	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Titin gene mutations are common in families with both peripartum cardiomyopathy and dilated cardiomyopathy.

van Spaendonck-Zwarts KY, Posafalvi A, van den Berg MP, Hilfiker-Kleiner D, Bollen IA, Sliwa K, Alders M, Almomani R, van Langen IM, van der Meer P, Sinke RJ, van der Velden J, Van Veldhuisen DJ, van Tintelen JP, Jongbloed JD.

Eur Heart J. 2014 Aug 21;35(32):2165-73. doi: 10.1093/eurheartj/ehu050. Epub 2014 Feb 20.

PubMed [citation]

PMID:: 24558114

See all PubMed Citations (9)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000272796.3

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

Description

proposed classification - variant undergoing re-assessment, contact laboratory

#	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		1	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004021283.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Variant summary: TTN c.835C>T (p.Arg279Trp) results in a non-conservative amino acid change located in the Z-disk region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 282792 control chromosomes, predominantly at a frequency of 0.00036 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00039), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.835C>T has been reported in the literature in multiple individuals affected with TTN-related conditions without strong evidence for causality (e.g., Lange_2005, Campuzan_2015, Sanchez_2016, van Spaendonck-Zwart_2014). At-least two co-occurrences with other pathogenic variant(s) have been reported in cis with this variant (TTN c.87491C>T, p.Pro29164Leu, Lange_2005; c.69086_69095del10, p.Arg23029ThrfsX9, van Spaendonck-Zwart_2014), providing supporting evidence for a benign role. Two publications report experimental evidence evaluating an impact on protein function, demonstrating reduced binding to nbd1 in mutant cells (Lange_2005, Chaveau_2014). However, neither study provides quantitative data indicating the strength of the effect. The following publications have been ascertained in the context of this evaluation (PMID: 26516846, 24105469, 24569025, 24578547, 27930701, 20708934, 24558114, 15802564, 24271327, 24231549). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Six submitters classified the variant as a variant of uncertain significance, and two classified it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

#	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 8, 2024

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