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NM_001267550.2(TTN):c.29042-2A>C AND Primary dilated cardiomyopathy

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Oct 8, 2014
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:
RCV000209530.5

Allele description [Variation Report for NM_001267550.2(TTN):c.29042-2A>C]

NM_001267550.2(TTN):c.29042-2A>C

Gene:
TTN:titin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.29042-2A>C
HGVS:
  • NC_000002.12:g.178706956T>G
  • NG_011618.3:g.128847A>C
  • NM_001256850.1:c.28091-2A>C
  • NM_001267550.2:c.29042-2A>CMANE SELECT
  • NM_003319.4:c.13282+31126A>C
  • NM_133378.4:c.25310-2A>C
  • NM_133432.3:c.13657+31126A>C
  • NM_133437.4:c.13858+31126A>C
  • LRG_391t1:c.29042-2A>C
  • LRG_391:g.128847A>C
  • NC_000002.11:g.179571683T>G
Links:
dbSNP: rs6716782
NCBI 1000 Genomes Browser:
rs6716782
Molecular consequence:
  • NM_003319.4:c.13282+31126A>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133432.3:c.13657+31126A>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133437.4:c.13858+31126A>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001256850.1:c.28091-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001267550.2:c.29042-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_133378.4:c.25310-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:
Primary dilated cardiomyopathy (DCM)
Synonyms:
Dilated Cardiomyopathy
Identifiers:
EFO: EFO_0000407; MONDO: MONDO:0005021; MeSH: D002311; MedGen: C0007193; Human Phenotype Ontology: HP:0001644

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000189753Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust - JHS cohort
criteria provided, single submitter

(Roberts et al. 2015)		Uncertain significance
(Oct 8, 2014) 		germlineresearch

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineno3not providednot provided1980not providedresearch
not providedgermlineyes1not providednot provided374not providedresearch

Citations

PubMed

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.

Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, Mazzarotto F, Felkin LE, Gong S, MacArthur JA, Cunningham F, Flannick J, Gabriel SB, Altshuler DM, Macdonald PS, Heinig M, Keogh AM, Hayward CS, et al.

Sci Transl Med. 2015 Jan 14;7(270):270ra6. doi: 10.1126/scitranslmed.3010134.

PubMed [citation]
PMID:
25589632
PMCID:
PMC4560092

Details of each submission

From Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust - Unselected DCM, SCV000189635.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearch PubMed (1)

Description

This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon with intermediate levels of cardiac expression. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes374not providednot provided1not providednot providednot provided

From Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust - JHS cohort, SCV000189753.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedresearch PubMed (1)

Description

This TTN truncating variant (TTNtv) was identified in three individuals in this cohort and is located in an exon with intermediate levels of cardiac expression. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineno1980not providednot provided3not providednot providednot provided

Flagged submissions

Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000189635Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust - Unselected DCM
flagged submission
Reason: Claim with insufficient supporting evidence
Notes: None

(Roberts et al. 2015)		Likely pathogenic
(Oct 8, 2014) 		germlineresearch

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

Citation Link

Last Updated: Apr 6, 2024