NM_001267550.2(TTN):c.81321C>G (p.Tyr27107Ter) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 7, 2021
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:: RCV002345521.2

Allele description [Variation Report for NM_001267550.2(TTN):c.81321C>G (p.Tyr27107Ter)]

NM_001267550.2(TTN):c.81321C>G (p.Tyr27107Ter)

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.81321C>G (p.Tyr27107Ter)

HGVS:

NC_000002.12:g.178564811G>C
NG_011618.3:g.270992C>G
NG_051363.1:g.46985G>C
NM_001256850.1:c.76398C>G
NM_001267550.2:c.81321C>GMANE SELECT
NM_003319.4:c.54126C>G
NM_133378.4:c.73617C>G
NM_133432.3:c.54501C>G
NM_133437.4:c.54702C>G
NP_001243779.1:p.Tyr25466Ter
NP_001254479.2:p.Tyr27107Ter
NP_003310.4:p.Tyr18042Ter
NP_596869.4:p.Tyr24539Ter
NP_597676.3:p.Tyr18167Ter
NP_597681.4:p.Tyr18234Ter
LRG_391t1:c.81321C>G
LRG_391:g.270992C>G
NC_000002.11:g.179429538G>C
NM_001256850.1:c.76398C>G
NM_003319.4:c.54126C>G
p.Tyr24539X

Protein change:

Y18042*

Links:

dbSNP: rs557312035

NCBI 1000 Genomes Browser:

rs557312035

Molecular consequence:

NM_001256850.1:c.76398C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001267550.2:c.81321C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_003319.4:c.54126C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_133378.4:c.73617C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_133432.3:c.54501C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_133437.4:c.54702C>G - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002653985	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002653985

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 7, 2021)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.

Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, Mazzarotto F, Felkin LE, Gong S, MacArthur JA, Cunningham F, Flannick J, Gabriel SB, Altshuler DM, Macdonald PS, Heinig M, Keogh AM, Hayward CS, et al.

Sci Transl Med. 2015 Jan 14;7(270):270ra6. doi: 10.1126/scitranslmed.3010134.

PubMed [citation]

PMID:: 25589632
PMCID:: PMC4560092

Details of each submission

From Ambry Genetics, SCV002653985.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The p.Y18042* pathogenic mutation (also known as c.54126C>G), located in coding exon 153 of the TTN gene, results from a C to G substitution at nucleotide position 54126. This changes the amino acid from a tyrosine 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 (described as NM_001267550.1:c.81321C>G p.Y27107X) was identified in a cohort of individuals with dilated cardiomyopathy (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

ClinVar

Relating variation to medicine