ClinVar Genomic variation as it relates to human health
NM_001267550.2(TTN):c.102523C>T (p.Arg34175Ter)
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
-
NM_001267550.2(TTN):c.102523C>T (p.Arg34175Ter)
Variation ID: 464497 Accession: VCV000464497.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q31.2 2: 178534092 (GRCh38) [ NCBI UCSC ] 2: 179398819 (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 15, 2018 May 1, 2024 Dec 6, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001267550.2:c.102523C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001254479.2:p.Arg34175Ter nonsense NM_001256850.1:c.97600C>T NP_001243779.1:p.Arg32534Ter nonsense NM_003319.4:c.75328C>T NP_003310.4:p.Arg25110Ter nonsense NM_133378.4:c.94819C>T NP_596869.4:p.Arg31607Ter nonsense NM_133432.3:c.75703C>T NP_597676.3:p.Arg25235Ter nonsense NM_133437.4:c.75904C>T NP_597681.4:p.Arg25302Ter nonsense NC_000002.12:g.178534092G>A NC_000002.11:g.179398819G>A NG_011618.3:g.301711C>T NG_051363.1:g.16266G>A LRG_391:g.301711C>T - Protein change
- R34175*, R25110*, R25235*, R32534*, R25302*, R31607*
- Other names
- -
- Canonical SPDI
- NC_000002.12:178534091:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00002
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 | ||
---|---|---|---|---|---|---|
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 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
11726 | 31219 | |
TTN-AS1 | - | - | - | GRCh38 | - | 17891 |
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. |
---|---|---|---|---|
Pathogenic (1) |
criteria provided, single submitter
|
Dec 6, 2023 | RCV000534053.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 25, 2017 | RCV000624259.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
May 18, 2023 | RCV003302825.2 |
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. |
More information
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
(Jul 25, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000740491.1
First in ClinVar: Apr 15, 2018 Last updated: Apr 15, 2018 |
|
|
Pathogenic
(Dec 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Invitae
Accession: SCV000639026.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg34175*) 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.Arg34175*) 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 (rs752697861, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy, congenital myopathy, and/or muscular dystrophy with scoliosis (PMID: 24105469, 25163546, 27868403, 28611029, 32998006, 36264615). This variant is also known as c.C75904T, p.R25302X. ClinVar contains an entry for this variant (Variation ID: 464497). 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). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Likely pathogenic
(May 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004005943.2
First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024 |
Comment:
The p.R25110* variant (also known as c.75328C>T), located in coding exon 185 of the TTN gene, results from a C to T substitution at nucleotide … (more)
The p.R25110* variant (also known as c.75328C>T), located in coding exon 185 of the TTN gene, results from a C to T substitution at nucleotide position 75328. 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 variant (also referred to as p.Arg34175*) has been reported to co-occur with two other presumed truncating variants in TTN in individuals with childhood-onset skeletal myopathy with and without cardiomyopathy (Chauveau C et al. Hum Mol Genet, 2014 Feb;23:980-91; Park HJ et al. J Clin Neurol, 2017 Jan;13:116-118). This variant has also been detected in the presumed heterozygous state in an individual with dilated cardiomyopathy and in cohorts not selected for the presence of skeletal myopathy or cardiovascular disease; however, details were limited (Haggerty CM et al. Circulation. 2019 Jul;140(1):42-54; Haskell GT et al. Circ Cardiovasc Genet, 2017 Jun;10; Park J et al. Nat Med. 2021 Jan;27(1):66-72). 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 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. (less)
|
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 |
---|---|---|---|---|
Prevalence and Disease Expression of Pathogenic and Likely Pathogenic Variants Associated With Inherited Cardiomyopathies in the General Population. | Bourfiss M | Circulation. Genomic and precision medicine | 2022 | PMID: 36264615 |
Exome-wide evaluation of rare coding variants using electronic health records identifies new gene-phenotype associations. | Park J | Nature medicine | 2021 | PMID: 33432171 |
Discovery of TITIN Gene Truncating Variant Mutations and 5-Year Outcomes in Patients With Nonischemic Dilated Cardiomyopathy. | Anderson JL | The American journal of cardiology | 2020 | PMID: 32998006 |
Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the TTN Gene. | Akhtar MM | Circulation. Heart failure | 2020 | PMID: 32964742 |
Genomics-First Evaluation of Heart Disease Associated With Titin-Truncating Variants. | Haggerty CM | Circulation | 2019 | PMID: 31216868 |
Whole Exome Sequencing Identifies Truncating Variants in Nuclear Envelope Genes in Patients With Cardiovascular Disease. | Haskell GT | Circulation. Cardiovascular genetics | 2017 | PMID: 28611029 |
Titin-truncating variants affect heart function in disease cohorts and the general population. | Schafer S | Nature genetics | 2017 | PMID: 27869827 |
Clinical and Pathological Findings of a Korean Family with Pathogenic Variants of the TTN Gene. | Park HJ | Journal of clinical neurology (Seoul, Korea) | 2017 | PMID: 27868403 |
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 |
Atlas of the clinical genetics of human dilated cardiomyopathy. | Haas J | European heart journal | 2015 | PMID: 25163546 |
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 |
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 |
click to load more click to collapse |
Text-mined citations for rs752697861 ...
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.