ClinVar Genomic variation as it relates to human health
NM_001267550.2(TTN):c.107800G>T (p.Gly35934Ter)
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.
Likely pathogenic(1); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001267550.2(TTN):c.107800G>T (p.Gly35934Ter)
Variation ID: 282175 Accession: VCV000282175.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q31.2 2: 178527188 (GRCh38) [ NCBI UCSC ] 2: 179391915 (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 19, 2017 Feb 28, 2024 Dec 22, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001267550.2:c.107800G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001254479.2:p.Gly35934Ter nonsense NM_001256850.1:c.102877G>T NP_001243779.1:p.Gly34293Ter nonsense NM_003319.4:c.80605G>T NP_003310.4:p.Gly26869Ter nonsense NM_133378.4:c.100096G>T NP_596869.4:p.Gly33366Ter nonsense NM_133432.3:c.80980G>T NP_597676.3:p.Gly26994Ter nonsense NM_133437.4:c.81181G>T NP_597681.4:p.Gly27061Ter nonsense NC_000002.12:g.178527188C>A NC_000002.11:g.179391915C>A NG_011618.3:g.308615G>T NG_051363.1:g.9362C>A LRG_391:g.308615G>T - Protein change
- G34293*, G33366*, G35934*, G26869*, G26994*, G27061*
- Other names
- -
- Canonical SPDI
- NC_000002.12:178527187:C: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
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 |
11660 | 30937 | |
TTN-AS1 | - | - | - | GRCh38 | - | 17689 |
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. |
---|---|---|---|---|
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 31, 2017 | RCV000725043.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 22, 2023 | RCV001227213.7 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Jul 30, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000333491.3
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
Uncertain significance
(Oct 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000570208.3
First in ClinVar: Apr 27, 2017 Last updated: Dec 19, 2017 |
Comment:
The G34293X variant of uncertain significance in the TTN gene has not been reported as pathogenic or benign to our knowledge. This variant is not … (more)
The G34293X variant of uncertain significance in the TTN gene has not been reported as pathogenic or benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In addition, G34293X is expected to result in an abnormal, truncated protein product. While other truncating variants in the TTN gene have been reported in the Human Gene Mutation Database in association with DCM (Stenson et al., 2014), these variants are all located upstream of G34293X. Furthermore, this variant is not located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Other truncating variants in the M-band of titin, where this variant occurs, have been reported in association with an autosomal recessive early-onset myopathy with cardiomyopathy (Carmignac et al., 2007), and heterozygous parents were reportedly healthy. Moreover, other nonsense and frameshift TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). (less)
|
|
Likely pathogenic
(Dec 22, 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: SCV001399561.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gly35934*) 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.Gly35934*) 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 0.0009%). This premature translational stop signal has been observed in individual(s) with TTN-related conditions (PMID: 28449774, 31561939, 35177841). This variant is also known as p.G26869X. ClinVar contains an entry for this variant (Variation ID: 282175). 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)
|
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 |
---|---|---|---|---|
Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank. | Jurgens SJ | Nature genetics | 2022 | PMID: 35177841 |
Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the TTN Gene. | Akhtar MM | Circulation. Heart failure | 2020 | PMID: 32964742 |
Genetic and phenotypic characterisation of inherited myopathies in a tertiary neuromuscular centre. | Bugiardini E | Neuromuscular disorders : NMD | 2019 | PMID: 31561939 |
Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome. | Lahrouchi N | Journal of the American College of Cardiology | 2017 | PMID: 28449774 |
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 rs368277535 ...
HelpRecord last updated Mar 05, 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.