NM_001267550.2(TTN):c.40963G>T (p.Glu13655Ter) AND Cardiovascular phenotype

Clinical significance:Likely pathogenic (Last evaluated: Sep 13, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_001267550.2(TTN):c.40963G>T (p.Glu13655Ter)]

NM_001267550.2(TTN):c.40963G>T (p.Glu13655Ter)

TTN:titin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.40963G>T (p.Glu13655Ter)
  • NC_000002.12:g.178636764C>A
  • NG_011618.3:g.199039G>T
  • NM_001256850.1:c.36040G>T
  • NM_001267550.2:c.40963G>TMANE SELECT
  • NM_003319.4:c.13768G>T
  • NM_133378.4:c.33259G>T
  • NM_133432.3:c.14143G>T
  • NM_133437.4:c.14344G>T
  • NP_001243779.1:p.Glu12014Ter
  • NP_001254479.2:p.Glu13655Ter
  • NP_003310.4:p.Glu4590Ter
  • NP_596869.4:p.Glu11087Ter
  • NP_597676.3:p.Glu4715Ter
  • NP_597681.4:p.Glu4782Ter
  • LRG_391:g.199039G>T
  • NC_000002.11:g.179501491C>A
  • NP_596869.4:p.Glu11087*
Protein change:
dbSNP: rs727504198
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001256850.1:c.36040G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001267550.2:c.40963G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_003319.4:c.13768G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133378.4:c.33259G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133432.3:c.14143G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_133437.4:c.14344G>T - nonsense - [Sequence Ontology: SO:0001587]


Cardiovascular phenotype
MedGen: CN230736

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000737324Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Sep 13, 2019)
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, SCV000737324.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided


The p.E4590* variant (also known as c.13768G>T), located in coding exon 52 of the TTN gene, results from a G to T substitution at nucleotide position 13768. This changes the amino acid from a glutamic acid to a stop codon within coding exon 52. This exon is located in the I-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 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.

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

Last Updated: Apr 12, 2021

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