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NM_001267550.2(TTN):c.70162C>T (p.Arg23388Ter) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Aug 7, 2023
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:
RCV002327000.3

Allele description [Variation Report for NM_001267550.2(TTN):c.70162C>T (p.Arg23388Ter)]

NM_001267550.2(TTN):c.70162C>T (p.Arg23388Ter)

Genes:
LOC126806422:BRD4-independent group 4 enhancer GRCh37_chr2:179440205-179441404 [Gene]
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.70162C>T (p.Arg23388Ter)
Other names:
p.R21747*:CGA>TGA
HGVS:
  • NC_000002.12:g.178575970G>A
  • NG_011618.3:g.259833C>T
  • NG_051363.1:g.58144G>A
  • NM_001256850.1:c.65239C>T
  • NM_001267550.2:c.70162C>TMANE SELECT
  • NM_003319.4:c.42967C>T
  • NM_133378.4:c.62458C>T
  • NM_133432.3:c.43342C>T
  • NM_133437.4:c.43543C>T
  • NP_001243779.1:p.Arg21747Ter
  • NP_001254479.2:p.Arg23388Ter
  • NP_003310.4:p.Arg14323Ter
  • NP_596869.4:p.Arg20820Ter
  • NP_597676.3:p.Arg14448Ter
  • NP_597681.4:p.Arg14515Ter
  • LRG_391:g.259833C>T
  • NC_000002.11:g.179440697G>A
  • NM_001267550.1:c.70162C>T
  • NM_003319.4:c.42967C>T
  • p.Arg20820*
Protein change:
R14323*
Links:
dbSNP: rs781540455
NCBI 1000 Genomes Browser:
rs781540455
Molecular consequence:
  • NM_001256850.1:c.65239C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001267550.2:c.70162C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_003319.4:c.42967C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133378.4:c.62458C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133432.3:c.43342C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133437.4:c.43543C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002626693Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Aug 7, 2023) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy.

Sedaghat-Hamedani F, Haas J, Zhu F, Geier C, Kayvanpour E, Liss M, Lai A, Frese K, Pribe-Wolferts R, Amr A, Li DT, Samani OS, Carstensen A, Bordalo DM, Müller M, Fischer C, Shao J, Wang J, Nie M, Yuan L, Haßfeld S, Schwartz C, et al.

Eur Heart J. 2017 Dec 7;38(46):3449-3460. doi: 10.1093/eurheartj/ehx545.

PubMed [citation]
PMID:
29029073

Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation.

Choi SH, Weng LC, Roselli C, Lin H, Haggerty CM, Shoemaker MB, Barnard J, Arking DE, Chasman DI, Albert CM, Chaffin M, Tucker NR, Smith JD, Gupta N, Gabriel S, Margolin L, Shea MA, Shaffer CM, Yoneda ZT, Boerwinkle E, Smith NL, Silverman EK, et al.

JAMA. 2018 Dec 11;320(22):2354-2364. doi: 10.1001/jama.2018.18179.

PubMed [citation]
PMID:
30535219
PMCID:
PMC6436530
See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002626693.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

The p.R14323* variant (also known as c.42967C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 42967. This changes the amino acid from an arginine to a stop codon within coding exon 153. This exon 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 variant (also referred to as NM_001267550:c.70162C>T, p.R23388X) has been detected in a left ventricular non-compaction cohort, an early onset atrial fibrillation cohort, and in an individual with dilated cardiomyopathy (Sedaghat-Hamedani F et al. Eur Heart J, 2017 Dec;38:3449-3460; Choi SH et al. JAMA, 2018 12;320:2354-2364; Brown EE et al. Circ Genom Precis Med. 2020 Dec;13(6):e003082). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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). As such, this alteration is classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 26, 2024