NM_001267550.2(TTN):c.93166C>T (p.Arg31056Ter) AND Cardiovascular phenotype

Clinical significance:Pathogenic (Last evaluated: Apr 10, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000619547.1

Allele description [Variation Report for NM_001267550.2(TTN):c.93166C>T (p.Arg31056Ter)]

NM_001267550.2(TTN):c.93166C>T (p.Arg31056Ter)

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.93166C>T (p.Arg31056Ter)
HGVS:
  • NC_000002.12:g.178548460G>A
  • NG_011618.3:g.287343C>T
  • NG_051363.1:g.30634G>A
  • NM_001256850.1:c.88243C>T
  • NM_001267550.2:c.93166C>TMANE SELECT
  • NM_003319.4:c.65971C>T
  • NM_133378.4:c.85462C>T
  • NM_133432.3:c.66346C>T
  • NM_133437.4:c.66547C>T
  • NP_001243779.1:p.Arg29415Ter
  • NP_001254479.2:p.Arg31056Ter
  • NP_003310.4:p.Arg21991Ter
  • NP_596869.4:p.Arg28488Ter
  • NP_597676.3:p.Arg22116Ter
  • NP_597681.4:p.Arg22183Ter
  • LRG_391t1:c.93166C>T
  • LRG_391:g.287343C>T
  • NC_000002.11:g.179413187G>A
Protein change:
R21991*
Links:
dbSNP: rs72648250
NCBI 1000 Genomes Browser:
rs72648250
Molecular consequence:
  • NM_001256850.1:c.88243C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001267550.2:c.93166C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_003319.4:c.65971C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133378.4:c.85462C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133432.3:c.66346C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133437.4:c.66547C>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
SCV000735415Ambry Geneticscriteria provided, single submitter
Pathogenic
(Apr 10, 2019)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Truncations of titin causing dilated cardiomyopathy.

Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, et al.

N Engl J Med. 2012 Feb 16;366(7):619-28. doi: 10.1056/NEJMoa1110186.

PubMed [citation]
PMID:
22335739
PMCID:
PMC3660031

Poor prognosis of rare sarcomeric gene variants in patients with dilated cardiomyopathy.

Merlo M, Sinagra G, Carniel E, Slavov D, Zhu X, Barbati G, Spezzacatene A, Ramani F, Salcedo E, Di Lenarda A, Mestroni L, Taylor MR; Familial Cardiomyopathy Registry..

Clin Transl Sci. 2013 Dec;6(6):424-8. doi: 10.1111/cts.12116. Epub 2013 Oct 3.

PubMed [citation]
PMID:
24119082
PMCID:
PMC3865161
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000735415.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (4)

Description

The p.R21991* pathogenic mutation (also known as c.65971C>T), located in coding exon 166 of the TTN gene, results from a C to T substitution at nucleotide position 65971. This changes the amino acid from an arginine to a stop codon within coding exon 166. This variant is located in the A-band region of the N2-B isoform of the titin protein, and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This truncating alteration has been reported in unrelated individuals with dilated cardiomyopathy (DCM) and has been reported to segregate with disease in families (Herman DS et al. N Engl J Med. 2012;366(7):619-28; Franaszczyk M. PLoS ONE. 2017;12(1):e0169007). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Nov 27, 2021

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