VCV000446427.12 - ClinVar

NM_001267550.2(TTN):c.64011C>A (p.Tyr21337Ter)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (2); Likely pathogenic (2)

4 out of 4 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001267550.2(TTN):c.64011C>A (p.Tyr21337Ter)

Variation ID: 446427 Accession: VCV000446427.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q31.2 2: 178587200 (GRCh38) [ NCBI UCSC ] 2: 179451927 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 3, 2017	Feb 23, 2026	Dec 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001267550.2:c.64011C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001254479.2:p.Tyr21337Ter	nonsense
NM_001256850.1:c.59088C>A	NP_001243779.1:p.Tyr19696Ter	nonsense
NM_003319.4:c.36816C>A	NP_003310.4:p.Tyr12272Ter	nonsense
NM_133378.4:c.56307C>A	NP_596869.4:p.Tyr18769Ter	nonsense
NM_133432.3:c.37191C>A	NP_597676.3:p.Tyr12397Ter	nonsense
NM_133437.4:c.37392C>A	NP_597681.4:p.Tyr12464Ter	nonsense
NC_000002.12:g.178587200G>T
NC_000002.11:g.179451927G>T
NG_011618.3:g.248603C>A
NG_051363.1:g.69374G>T
LRG_391:g.248603C>A

... more HGVS ... less HGVS

Protein change

Y21337*, Y12397*, Y12272*, Y19696*, Y18769*, Y12464*

Other names

Canonical SPDI

NC_000002.12:178587199:G:T

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA349446699 dbSNP: rs1553636324 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TTN		Some evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	14964	39957
TTN-AS1	-	-	-	GRCh38	-	22954

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Dilated cardiomyopathy 1G	Likely pathogenic (1)	criteria provided, single submitter	Aug 9, 2017	RCV000515670.3
Autosomal recessive limb-girdle muscular dystrophy type 2J Dilated cardiomyopathy 1G	Pathogenic (1)	criteria provided, single submitter	Dec 22, 2024	RCV000695044.9
Cardiovascular phenotype	Likely pathogenic (1)	criteria provided, single submitter	Dec 9, 2021	RCV002350135.2
Myopathy, myofibrillar, 9, with early respiratory failure	Pathogenic (1)	criteria provided, single submitter	Aug 2, 2022	RCV004771476.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Aug 09, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Dilated cardiomyopathy 1G	MVZ Martinsried, Medicover Genetics Accession: SCV000611779.1 First in ClinVar: Dec 03, 2017 Last updated: Dec 03, 2017	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Pathogenic (Dec 22, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Dilated cardiomyopathy 1G Autosomal recessive limb-girdle muscular dystrophy type 2J Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000823519.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 23, 2026	Publications: PubMed (4) PubMed: 23975875‚ 25589632‚ 28492532‚ 31737537 Comment: show This sequence change creates a premature translational stop signal (p.Tyr21337*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with clinical features of TTN-related conditions (PMID: 31737537; internal data). ClinVar contains an entry for this variant (Variation ID: 446427). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Dec 09, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002619177.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 31737537 Comment: show The p.Y12272* variant (also known as c.36816C>A), located in coding exon 134 of the TTN gene, results from a C to A substitution at nucleotide position 36816. This changes the amino acid from a tyrosine to a stop codon within coding exon 134. 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 was reported in an individual with suspected dilated cardiomyopathy (DCM); however, clinical details were not provided (Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). 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). As such, this alteration is classified as likely pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Aug 02, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Myopathy, myofibrillar, 9, with early respiratory failure	Institute of Immunology and Genetics Kaiserslautern Accession: SCV005382215.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: show ACMG Criteria: PVS1, PM2, PP5; Variant was found in heterozygous state. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: Myotonia (present) , Handgrip myotonia (present)

Comment:

This sequence change creates a premature translational stop signal (p.Tyr21337*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with clinical features of TTN-related conditions (PMID: 31737537; internal data). ClinVar contains an entry for this variant (Variation ID: 446427). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Y12272* variant (also known as c.36816C>A), located in coding exon 134 of the TTN gene, results from a C to A substitution at nucleotide position 36816. This changes the amino acid from a tyrosine to a stop codon within coding exon 134. 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 was reported in an individual with suspected dilated cardiomyopathy (DCM); however, clinical details were not provided (Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). 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). As such, this alteration is classified as likely pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders.	Marschall C	Cardiovascular diagnosis and therapy	2019	PMID: 31737537
Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.	Roberts AM	Science translational medicine	2015	PMID: 25589632
Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy.	Ceyhan-Birsoy O	Neurology	2013	PMID: 23975875

Text-mined citations for rs1553636324 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2026