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NM_001267550.2(TTN):c.59460G>A (p.Trp19820Ter) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Feb 3, 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:
RCV000622152.4

Allele description [Variation Report for NM_001267550.2(TTN):c.59460G>A (p.Trp19820Ter)]

NM_001267550.2(TTN):c.59460G>A (p.Trp19820Ter)

Genes:
LOC126806424:CDK7 strongly-dependent group 2 enhancer GRCh37_chr2:179456337-179457536 [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.59460G>A (p.Trp19820Ter)
HGVS:
  • NC_000002.12:g.178592545C>T
  • NG_011618.3:g.243258G>A
  • NG_051363.1:g.74719C>T
  • NM_001256850.1:c.54537G>A
  • NM_001267550.2:c.59460G>AMANE SELECT
  • NM_003319.4:c.32265G>A
  • NM_133378.4:c.51756G>A
  • NM_133432.3:c.32640G>A
  • NM_133437.4:c.32841G>A
  • NP_001243779.1:p.Trp18179Ter
  • NP_001254479.2:p.Trp19820Ter
  • NP_003310.4:p.Trp10755Ter
  • NP_596869.4:p.Trp17252Ter
  • NP_597676.3:p.Trp10880Ter
  • NP_597681.4:p.Trp10947Ter
  • LRG_391:g.243258G>A
  • NC_000002.11:g.179457272C>T
  • NM_133378.4:c.51756G>A
Protein change:
W10755*
Links:
dbSNP: rs1250461669
NCBI 1000 Genomes Browser:
rs1250461669
Molecular consequence:
  • NM_001256850.1:c.54537G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001267550.2:c.59460G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_003319.4:c.32265G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133378.4:c.51756G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133432.3:c.32640G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133437.4:c.32841G>A - 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
SCV000736905Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Feb 3, 2023) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

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

Details of each submission

From Ambry Genetics, SCV000736905.6

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

Description

The p.W10755* variant (also known as c.32265G>A), located in coding exon 128 of the TTN gene, results from a G to A substitution at nucleotide position 32265. This changes the amino acid from a tryptophan to a stop codon within coding exon 128. 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 (referred to as c.59460G>A, p.W19820*) was detected in an early-onset atrial fibrillation cohort (Choi SH et al. JAMA, 2018 12;320:2354-2364). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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 majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Sep 29, 2024