ClinVar Genomic variation as it relates to human health
NM_001267550.2(TTN):c.105754C>T (p.Arg35252Ter)
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.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001267550.2(TTN):c.105754C>T (p.Arg35252Ter)
Variation ID: 288511 Accession: VCV000288511.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q31.2 2: 178530861 (GRCh38) [ NCBI UCSC ] 2: 179395588 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 6, 2016 May 1, 2024 Dec 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001267550.2:c.105754C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001254479.2:p.Arg35252Ter nonsense NM_001256850.1:c.100831C>T NP_001243779.1:p.Arg33611Ter nonsense NM_001267550.1:c.105754C>T NM_003319.4:c.78559C>T NP_003310.4:p.Arg26187Ter nonsense NM_133378.4:c.98050C>T NP_596869.4:p.Arg32684Ter nonsense NM_133432.3:c.78934C>T NP_597676.3:p.Arg26312Ter nonsense NM_133437.4:c.79135C>T NP_597681.4:p.Arg26379Ter nonsense NC_000002.12:g.178530861G>A NC_000002.11:g.179395588G>A NG_011618.3:g.304942C>T NG_051363.1:g.13035G>A LRG_391:g.304942C>T - Protein change
- R35252*, R32684*, R33611*, R26312*, R26379*, R26187*
- Other names
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- Canonical SPDI
- NC_000002.12:178530860:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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TTN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
11726 | 31218 | |
LOC129935183 | - | - | - | GRCh38 | - | 165 |
TTN-AS1 | - | - | - | GRCh38 | - | 17890 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 27, 2022 | RCV000432472.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 6, 2023 | RCV002519305.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 3, 2022 | RCV003165761.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 26, 2018 | RCV004017589.1 |
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. |
More information
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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. |
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Likely Pathogenic
(Jul 26, 2018)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848168.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg32684X variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/15278 African and 1/9842 Ashkenazi Jewish … (more)
The p.Arg32684X variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/15278 African and 1/9842 Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs886043924) and in ClinVar (Variation ID: 288511). This nonsense variant leads to a premature termination codon at position 32684, which is predicted to lead to a truncated or absent protein. The p.Arg32684X variant is located in M-band. Truncating variants in this domain are prevalent in the general population (Pugh 2014) but there is also some evidence linking them to disease. Homozygous frameshift variants have been described in two families with early onset myopathy and DCM (Carmignac 2007) and heterozygous truncating variants have been reported in individuals with tibial muscular dystrophy without cardiomyopathy (Hackman 2002, Hackman 2008). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg32684X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_Strong; PM2. (less)
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Likely pathogenic
(Jun 21, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000342639.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Likely pathogenic
(Dec 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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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.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003495511.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg35252*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg35252*) 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 present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of congenital myopathy (PMID: 35387801). ClinVar contains an entry for this variant (Variation ID: 288511). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Pathogenic
(May 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000534063.5
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; Located in the M-line region of TTN in which the majority of loss of function variants have been associated with autosomal recessive titinopathies (Carmignac et al., 2007); This variant is associated with the following publications: (PMID: 17444505) (less)
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Likely pathogenic
(Apr 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003812808.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Nov 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003860984.2
First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024 |
Comment:
The p.R26187* variant (also known as c.78559C>T), located in coding exon 185 of the TTN gene, results from a C to T substitution at nucleotide … (more)
The p.R26187* variant (also known as c.78559C>T), located in coding exon 185 of the TTN gene, results from a C to T substitution at nucleotide position 78559. This changes the amino acid from an arginine to a stop codon within coding exon 185. This exon is located in the M-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 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 M-band have been reported in association with autosomal recessive titinopathies, primarily presenting with skeletal myopathy phenotypes (Ceyhan-Birsoy O et al. Neurology. 2013 Oct 1;81(14):1205-14; De Cid R et al. Neurology. 2015;85(24):2126-35). In addition, regardless of their position, TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with dilated cardiomyopathy (DCM), though truncating variants in the A-band are the most common cause of 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; Schafer S et al. Nat. Genet., 2017 01;49:46-53). Based on the majority of available evidence to date, this variant is likely to be pathogenic in association with autosomal recessive titinopathy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear. (Carmignac V et al. Ann Neurol, 2007 Apr;61:340-51). (Nallamilli BRR et al. Ann Clin Transl Neurol, 2018 Dec;5:1574-1587). (less)
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Germline 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 germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Transcriptome-based variant calling and aberrant mRNA discovery enhance diagnostic efficiency for neuromuscular diseases. | Hong SE | Journal of medical genetics | 2022 | PMID: 35387801 |
Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the TTN Gene. | Akhtar MM | Circulation. Heart failure | 2020 | PMID: 32964742 |
Titin-truncating variants affect heart function in disease cohorts and the general population. | Schafer S | Nature genetics | 2017 | PMID: 27869827 |
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 |
Atypical phenotypes in titinopathies explained by second titin mutations. | Evilä A | Annals of neurology | 2014 | PMID: 24395473 |
Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. | Ceyhan-Birsoy O | Neurology | 2013 | PMID: 23975875 |
Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD). | Hackman P | Neuromuscular disorders : NMD | 2008 | PMID: 18948003 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TTN | - | - | - | - |
Text-mined citations for rs886043924 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.