NM_001267550.2(TTN):c.89017C>T (p.Arg29673Ter) AND Cardiovascular phenotype

Clinical significance:Likely pathogenic (Last evaluated: Nov 11, 2013)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000243308.1

Allele description [Variation Report for NM_001267550.2(TTN):c.89017C>T (p.Arg29673Ter)]

NM_001267550.2(TTN):c.89017C>T (p.Arg29673Ter)

Genes:
TTN-AS1:TTN antisense RNA 1 [Gene - HGNC]
TTN:titin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.89017C>T (p.Arg29673Ter)
HGVS:
  • NC_000002.12:g.178554094G>A
  • NG_011618.3:g.281709C>T
  • NG_051363.1:g.36268G>A
  • NM_001256850.1:c.84094C>T
  • NM_001267550.2:c.89017C>TMANE SELECT
  • NM_003319.4:c.61822C>T
  • NM_133378.4:c.81313C>T
  • NM_133432.3:c.62197C>T
  • NM_133437.4:c.62398C>T
  • NP_001243779.1:p.Arg28032Ter
  • NP_001254479.2:p.Arg29673Ter
  • NP_003310.4:p.Arg20608Ter
  • NP_596869.4:p.Arg27105Ter
  • NP_597676.3:p.Arg20733Ter
  • NP_597681.4:p.Arg20800Ter
  • LRG_391:g.281709C>T
  • NC_000002.11:g.179418821G>A
Protein change:
R20608*
Links:
dbSNP: rs886038916
NCBI 1000 Genomes Browser:
rs886038916
Molecular consequence:
  • NM_001256850.1:c.84094C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001267550.2:c.89017C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_003319.4:c.61822C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133378.4:c.81313C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133432.3:c.62197C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133437.4:c.62398C>T - nonsense - [Sequence Ontology: SO:0001587]
Observations:
1

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000319101Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Nov 11, 2013)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Details of each submission

From Ambry Genetics, SCV000319101.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The p.R27105X variant (also known as c.81313C>T) is located in coding exon 281 of the TTNgene. This alteration results from a C to T substitution at nucleotide position 81313. This changes the amino acid from an arginine to a stop codon within coding exon 281. Premature stop codons resulting in a truncated protein substantially alter protein structure, and this variant therefore meets ACMG criteria for classification as a mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med.2008;10:294). Furthermore, truncating alterations in TTN were observed at a significantly higher frequency among patients with dilated cardiomyopathy (DCM), 54/203 (27%), compared to patients with hypertrophic cardiomyopathy (3/231, 1%, P=9x10-14) and healthy controls (7 of 247, 3%, P=4x10-5). Among families with multiple relatives with DCM, this study also provided strong data demonstrating segregation with disease (Herman DS etal. N Eng J Med. 2012;366:619-628). However, the functional consequence of protein truncating alterations in TTN have not been well described, and this specific alteration (TTNp.R27105X) has not been reported in the literature.In addition, this variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), the 1000 Genomes Project and the NHLBI Exome Sequencing Project (ESP). In the ESP, this variant was not reported in 6042 samples (12084 alleles) with coverage at this position.Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, due to the uncertainty of the functional and clinical consequences, its significance remains unclear.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: May 10, 2021

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