NM_001267550.2(TTN):c.85090C>T (p.Arg28364Ter) AND Cardiovascular phenotype

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 9, 2025
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000243897.8

Allele description [Variation Report for NM_001267550.2(TTN):c.85090C>T (p.Arg28364Ter)]

NM_001267550.2(TTN):c.85090C>T (p.Arg28364Ter)

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.85090C>T (p.Arg28364Ter)

HGVS:

NC_000002.12:g.178561042G>A
NG_011618.3:g.274761C>T
NG_051363.1:g.43216G>A
NM_001256850.1:c.80167C>T
NM_001267550.2:c.85090C>TMANE SELECT
NM_003319.4:c.57895C>T
NM_133378.4:c.77386C>T
NM_133432.3:c.58270C>T
NM_133437.4:c.58471C>T
NP_001243779.1:p.Arg26723Ter
NP_001254479.2:p.Arg28364Ter
NP_003310.4:p.Arg19299Ter
NP_596869.4:p.Arg25796Ter
NP_597676.3:p.Arg19424Ter
NP_597681.4:p.Arg19491Ter
LRG_391t1:c.85090C>T
LRG_391:g.274761C>T
NC_000002.11:g.179425769G>A
NM_001267550.1:c.85090C>T
NM_133378.4:c.77386C>T

Protein change:

R19299*

Links:

dbSNP: rs770038577

Molecular consequence:

NM_001256850.1:c.80167C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001267550.2:c.85090C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_003319.4:c.57895C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133378.4:c.77386C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133432.3:c.58270C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133437.4:c.58471C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000320220	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 18, 2025)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30371277, 30535219 Citation Link,
SCV007542146	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 9, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000320220

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 18, 2025)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV007542146

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 9, 2025)

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Genotype-Positive Status Is Associated With Poor Prognoses in Patients With Left Ventricular Noncompaction Cardiomyopathy.

Li S, Zhang C, Liu N, Bai H, Hou C, Wang J, Song L, Pu J.

J Am Heart Assoc. 2018 Oct 16;7(20):e009910. doi: 10.1161/JAHA.118.009910.

PubMed [citation]

PMID:: 30371277
PMCID:: PMC6474962

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, SCV000320220.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.R19299* pathogenic mutation (also known as c.57895C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 57895. 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 p.R28364* (c.85090C>T) and p.R26723* (c.80167C>T)) has been reported in dilated cardiomyopathy (DCM), left ventricular noncompaction, and early-onset atrial fibrillation cohorts (Roberts AM. Sci Transl Med 2015 Jan;7(270):270ra6; Choi SH et al. JAMA. 2018 12;320(22):2354-2364; Li S et al. J Am Heart Assoc, 2018 Oct;7:e009910; Ambry internal data). In addition, 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV007542146.1

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

Description

PVS1, PS4_supp, PM2

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

Last Updated: Jul 6, 2026

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