VCV001052047.10 - ClinVar

NM_001267550.2(TTN):c.104165C>T (p.Thr34722Ile)

Germline

Classification

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

Uncertain significance

2 out of 2 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.104165C>T (p.Thr34722Ile)

Variation ID: 1052047 Accession: VCV001052047.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q31.2 2: 178532450 (GRCh38) [ NCBI UCSC ] 2: 179397177 (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	Apr 13, 2021	Feb 23, 2026	Nov 11, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_001267550.2:c.104165C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001254479.2:p.Thr34722Ile	missense
NM_001256850.1:c.99242C>T	NP_001243779.1:p.Thr33081Ile	missense
NM_003319.4:c.76970C>T	NP_003310.4:p.Thr25657Ile	missense
NM_133378.4:c.96461C>T	NP_596869.4:p.Thr32154Ile	missense
NM_133432.3:c.77345C>T	NP_597676.3:p.Thr25782Ile	missense
NM_133437.4:c.77546C>T	NP_597681.4:p.Thr25849Ile	missense
NC_000002.12:g.178532450G>A
NC_000002.11:g.179397177G>A
NG_011618.3:g.303353C>T
NG_051363.1:g.14624G>A
LRG_391:g.303353C>T
LRG_391t1:c.104165C>T

... more HGVS ... less HGVS

Protein change

T25657I, T25782I, T25849I, T32154I, T33081I, T34722I

Other names

Canonical SPDI

NC_000002.12:178532449:G:A

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00003

Links

ClinGen: CA1985472 dbSNP: rs770151999 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	12602	33666
TTN-AS1	-	-	-	GRCh38	-	19367

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.
Autosomal recessive limb-girdle muscular dystrophy type 2J Dilated cardiomyopathy 1G	Uncertain significance (1)	criteria provided, single submitter	Nov 11, 2025	RCV001360163.9
not provided	Uncertain significance (1)	criteria provided, single submitter	Apr 21, 2022	RCV002293530.2

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.
Uncertain significance (Apr 21, 2022) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV002586638.2 First in ClinVar: Oct 29, 2022 Last updated: Mar 04, 2023	Comment: show Not observed at significant frequency in large population cohorts (gnomAD); Missense variant in a gene in which most reported pathogenic variants are truncating/loss of function; Has not been previously published as pathogenic or benign to our knowledge (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Nov 11, 2025) 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: SCV001556066.6 First in ClinVar: Apr 13, 2021 Last updated: Feb 23, 2026	Publications: PubMed (2) PubMed: 23975875‚ 25589632 Comment: show This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 34722 of the TTN protein (p.Thr34722Ile). This variant is present in population databases (rs770151999, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1052047). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is located in the M band of TTN (PMID: 25589632). Non-truncating variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (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

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); Missense variant in a gene in which most reported pathogenic variants are truncating/loss of function; Has not been previously published as pathogenic or benign to our knowledge

Comment:

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 34722 of the TTN protein (p.Thr34722Ile). This variant is present in population databases (rs770151999, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1052047). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is located in the M band of TTN (PMID: 25589632). Non-truncating variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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 rs770151999 ...

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