NM_001267550.2(TTN):c.9610C>T (p.Arg3204Ter) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 22, 2024
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:: RCV002446529.4

Allele description [Variation Report for NM_001267550.2(TTN):c.9610C>T (p.Arg3204Ter)]

NM_001267550.2(TTN):c.9610C>T (p.Arg3204Ter)

Gene:

TTN:titin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.9610C>T (p.Arg3204Ter)

HGVS:

NC_000002.12:g.178766474G>A
NG_011618.3:g.69329C>T
NM_001256850.1:c.9610C>T
NM_001267550.2:c.9610C>TMANE SELECT
NM_003319.4:c.9472C>T
NM_133378.4:c.9610C>T
NM_133379.5:c.9610C>T
NM_133432.3:c.9472C>T
NM_133437.4:c.9472C>T
NP_001243779.1:p.Arg3204Ter
NP_001254479.2:p.Arg3204Ter
NP_003310.4:p.Arg3158Ter
NP_596869.4:p.Arg3204Ter
NP_596870.2:p.Arg3204Ter
NP_597676.3:p.Arg3158Ter
NP_597681.4:p.Arg3158Ter
LRG_391:g.69329C>T
NC_000002.11:g.179631201G>A
NM_001267550.1:c.9610C>T
NM_003319.4:c.9472C>T

Protein change:

R3158*

Links:

dbSNP: rs757836789

NCBI 1000 Genomes Browser:

rs757836789

Molecular consequence:

NM_001256850.1:c.9610C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001267550.2:c.9610C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_003319.4:c.9472C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133378.4:c.9610C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133379.5:c.9610C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133432.3:c.9472C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133437.4:c.9472C>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
SCV002683233	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (May 22, 2024)	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

SCV002683233

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(May 22, 2024)

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

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, SCV002683233.4

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

Description

The p.R3158* variant (also known as c.9472C>T), located in coding exon 39 of the TTN gene, results from a C to T substitution at nucleotide position 9472. This changes the amino acid from an arginine to a stop codon within coding exon 39. 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 has been reported in a case control study looking at the correlation between TTN truncating alterations and atrial fibrillation (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, 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). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is classified as likely pathogenic.

#	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

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