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NM_001267550.2(TTN):c.43986T>G (p.Asp14662Glu)

Conflicting interpretations of pathogenicity​

Likely benign(1);Uncertain significance(3)

Review status:
criteria provided, conflicting interpretations
4 (Most recent: Apr 12, 2019)
Last evaluated:
Apr 13, 2018
Variation ID:
single nucleotide variant

NM_001267550.2(TTN):c.43986T>G (p.Asp14662Glu)

Allele ID
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
Genomic location
2: 178631062 (GRCh38) GRCh38 UCSC
2: 179495789 (GRCh37) GRCh37 UCSC
Nucleotide Protein Molecular
... more HGVS
Protein change
D12094E, D14662E, D13021E, D5597E, D5789E, D5722E
Other names
Canonical SPDI
Functional consequence
Global minor allele frequency (GMAF)
0.00020 (C)

Allele frequency
The Genome Aggregation Database (gnomAD), exomes 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
1000 Genomes Project 0.00020
ClinGen: CA1995783
dbSNP: rs201390600

Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Jun 5, 2014 RCV000244515.2
Uncertain significance 1 criteria provided, single submitter Aug 3, 2017 RCV000463022.2
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Apr 13, 2018 RCV000598397.2
Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
TTN Sufficient evidence for dosage pathogenicity No evidence available GRCh38
7638 17883

Submitted interpretations and evidence

(Last evaluated)
Review status
(Assertion criteria)
Submitter Supporting information
Uncertain significance
(Jun 05, 2014)
criteria provided, single submitter
Method: clinical testing
Hereditary disease
Allele origin: germline
Ambry Genetics
Accession: SCV000318159.3
Submitted: (Feb 08, 2018)
Evidence details
PubMed (14)
Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Uncertain significance
(Aug 03, 2017)
criteria provided, single submitter
Method: clinical testing
Dilated cardiomyopathy 1G
Limb-girdle muscular dystrophy, type 2J
Allele origin: germline
Accession: SCV000543064.2
Submitted: (Oct 05, 2017)
Evidence details
Uncertain significance
(Nov 17, 2016)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000703173.2
Submitted: (Sep 19, 2018)
Evidence details
Other databases…
Likely benign
(Apr 13, 2018)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
Accession: SCV000977570.1
Submitted: (Apr 12, 2019)
Evidence details
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)

Functional evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

Title Author Journal Year Link
Atypical phenotypes in titinopathies explained by second titin mutations. Evilä A Annals of neurology 2014 PMID: 24395473
Recessive TTN truncating mutations define novel forms of core myopathy with heart disease. Chauveau C Human molecular genetics 2014 PMID: 24105469
Autosomal recessive cortical myoclonic tremor and epilepsy: association with a mutation in the potassium channel associated gene CNTN2. Stogmann E Brain : a journal of neurology 2013 PMID: 23518707
Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy. Norton N Circulation. Cardiovascular genetics 2013 PMID: 23418287
Truncations of titin causing dilated cardiomyopathy. Herman DS The New England journal of medicine 2012 PMID: 22335739
Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes. Taylor M Circulation 2011 PMID: 21810661
Contribution of genetic factors to the pathogenesis of dilated cardiomyopathy: the cause of dilated cardiomyopathy: genetic or acquired? (genetic-side). Kimura A Circulation journal : official journal of the Japanese Circulation Society 2011 PMID: 21617319
Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD). Hackman P Neuromuscular disorders : NMD 2008 PMID: 18948003
C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Carmignac V Annals of neurology 2007 PMID: 17444505
Left ventricular systolic dysfunction and ischemic cardiomyopathy. Henry LB Critical care nursing quarterly 2003 PMID: 12669942
Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Hackman P American journal of human genetics 2002 PMID: 12145747
The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. Bang ML Circulation research 2001 PMID: 11717165
Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Satoh M Biochemical and biophysical research communications 1999 PMID: 10462489
Muscular dystrophy with separate clinical phenotypes in a large family. Udd B Muscle & nerve 1991 PMID: 1745277 - - - -

Text-mined citations for rs201390600...

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 Oct 08, 2021