ClinVar Genomic variation as it relates to human health
NM_001267550.2(TTN):c.40558+1G>A
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(10); Benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001267550.2(TTN):c.40558+1G>A
Variation ID: 223256 Accession: VCV000223256.46
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q31.2 2: 178642236 (GRCh38) [ NCBI UCSC ] 2: 179506963 (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 Mar 11, 2016 Oct 8, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001267550.2:c.40558+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001256850.1:c.35635+1G>A splice donor NM_003319.4:c.13363+1G>A splice donor NM_133378.4:c.32854+1G>A splice donor NM_133432.3:c.13738+1G>A splice donor NM_133437.4:c.13939+1G>A splice donor NC_000002.12:g.178642236C>T NC_000002.11:g.179506963C>T NG_011618.3:g.193567G>A LRG_391:g.193567G>A LRG_391t1:c.40558+1G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000002.12:178642235:C:T
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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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00012
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00017
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00006
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
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. |
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TTN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
11892 | 31612 |
Conditions - Germline
Condition
Help
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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Uncertain significance (1) |
criteria provided, single submitter
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Oct 8, 2014 | RCV000209704.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 11, 2023 | RCV000221188.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 27, 2023 | RCV000456920.12 | |
Uncertain significance (1) |
no assertion criteria provided
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Nov 13, 2015 | RCV000477783.3 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Mar 10, 2023 | RCV000725594.26 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 18, 2017 | RCV000770044.3 | |
Benign (1) |
criteria provided, single submitter
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Jan 12, 2019 | RCV001132686.5 | |
Benign (1) |
criteria provided, single submitter
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Jan 12, 2019 | RCV001132687.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2024 | RCV002381720.3 | |
TTN-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2019 | RCV004529009.1 |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 4, 2024 | RCV003992234.2 | |
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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
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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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Uncertain significance
(Oct 08, 2014)
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criteria provided, single submitter
Method: research
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Primary dilated cardiomyopathy
(Autosomal dominant inheritance)
Affected status: no
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Study: FHS cohort
Accession: SCV000189731.1 First in ClinVar: Mar 11, 2016 Last updated: Mar 11, 2016 |
Comment:
This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the … (more)
This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Jun 11, 2018)
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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: SCV000338006.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Uncertain significance
(Jan 18, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000272642.4
First in ClinVar: May 29, 2016 Last updated: Jul 03, 2020 |
Comment:
The c.32854+1G>A variant in TTN has been reported in 1 individual with DCM, and segregated with disease in 1 affected relative (Herman 2012). This variant … (more)
The c.32854+1G>A variant in TTN has been reported in 1 individual with DCM, and segregated with disease in 1 affected relative (Herman 2012). This variant has also been identified in 4/15632 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs368219776). The c.32854+1G>A variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Splice and other truncating variants in TTN are strongly associated with DCM, particularly if they are located in the exons encoding for the A-band region of the protein (Herman 2012, Pugh 2014). Variants in the I-band, where the c.32854+1G>A variant is located, occur at a greater frequency in controls than in individuals with DCM (Pugh 2014). This decreases the likelihood, but does not rule out that this variant has a role in disease. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the c.32854+1G>A variant is uncertain. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Apr 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000901470.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019 |
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Uncertain significance
(Jan 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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TTN-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914879.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The TTN c.32854+1G>A variant (also referred to as c. 40558+1G>A or c. 35635+1G>A) occurs in a canonical splice site (donor) and is therefore predicted to … (more)
The TTN c.32854+1G>A variant (also referred to as c. 40558+1G>A or c. 35635+1G>A) occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in two studies and is found in two individuals with dilated cardiomyopathy; it is not clear if they are related (Herman et al. 2012). This variant was also present in a presumable healthy individual (Roberts et al. 2015) and it is reported at a frequency of 0.0002559 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the c.32854+1G>A variant is classified as a variant of unknown significance but suspicious for pathogenicity for TTN-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Benign
(Jan 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Tibial muscular dystrophy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001292355.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Benign
(Jan 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Myopathy, myofibrillar, 9, with early respiratory failure
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001292354.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Likely pathogenic
(Dec 27, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000542903.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects a donor splice site in intron 219 of the TTN gene. It is expected to disrupt RNA splicing and likely results … (more)
This sequence change affects a donor splice site in intron 219 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. This variant is present in population databases (rs368219776, gnomAD 0.01%). This variant has not been observed in the literature in individuals with autosomal recessive TTN-related conditions. This variant has been reported in individual(s) with dilated cardiomyopathy (PMID: 22335739, 28333919, 30535219; Invitae); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 223256). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). 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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Uncertain significance
(Jul 01, 2021)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001747285.19
First in ClinVar: Jul 10, 2021 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 2
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Uncertain significance
(May 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003934117.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: TTN c.32854+1G>A is located in a canonical splice-site, and therefore could affect mRNA splicing resulting in a significantly altered protein due to either … (more)
Variant summary: TTN c.32854+1G>A is located in a canonical splice-site, and therefore could affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. The sequence of this splice site deviates from the consensus, therefore computational tools were not able to predict the impact of the variant on normal splicing, although one predicts the variant abolishes the 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant is located in the I-band region, neighboring a symmetric exon that is highly expressed in the heart (Roberts_2015). The variant allele was found at a frequency of 5.5e-05 in 234996 control chromosomes, predominantly at a frequency of 0.00013 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than the estimated maximum expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00039), allowing no conclusion about variant significance. The variant, c.32854+1G>A (aka c.40558+1G>A), has been reported in the literature in heterozygous state in at least three individuals affected with Dilated Cardiomyopathy (e.g. Herman_2012, Bagnall_2017), however in one of these cases other potentially causal co-occurring variants were also present. In addition, the variant was also reported in 3 / 13,131 asymptomatic individuals aged 70 years and older without a history of atherothrombotic cardiovascular disease events in the ASPREE study (Lacaze_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22335739, 25589632, 28333919, 30535219, 33226272, 34135346, 35177841). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence for independent evaluation, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Mar 10, 2023)
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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: SCV003825434.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1G
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809750.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Uncertain significance
(Jan 12, 2024)
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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: SCV002690366.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.13363+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 46 of the TTN gene. Coding exon 46 is … (more)
The c.13363+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 46 of the TTN gene. Coding exon 46 is located in the I-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 c.35635+1G>A and c.40558+1G>A) has been reported in dilated cardiomyopathy cohorts, but also in population-based cohorts and cohorts not selected for the presence of cardiomyopathy (Herman DS et al. N Engl J Med. 2012 Feb;366(7):619-28; Roberts AM et al. Sci Transl Med. 2015 Jan;7(270):270ra6; Connell PS et al. Circ Genom Precis Med. 2021 Feb;14(1):e003131; Lacaze P et al. NPJ Genom Med. 2021 Jun;6(1):51). This variant was detected in a sudden death victim reported to have dilated cardiomyopathy who also had variants in other cardiac-related genes, and this alteration did not segregate with disease in the family (Bagnall RD et al. Genet Med. 2017 Oct;19(10):1127-1133). This variant has also been detected in an early-onset atrial fibrillation cohort (Choi SH et al. JAMA. 2018 12;320(22):2354-2364). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing and often result in a transcript encoding a truncated protein. Truncating variants in the A-band of titin are the most common cause of dilated cardiomyopathy (DCM), and, regardless of their position, truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM (Herman DS et al. N. Engl. J. Med. 2012;366:619-28; Roberts AM et al. Sci Transl Med. 2015;7:270ra6; Schafer S et al. Nat. Genet. 2017;49:46-53). However, TTN truncating variants have also been reported in 1-3% of the general population (Herman DS et al. N. Engl. J. Med. 2012;366:619-28). Since the exact splicing impact of this alteration is unknown and supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Nov 13, 2015)
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no assertion criteria provided
Method: research
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Dilated cardiomyopathy 1G
Tibial muscular dystrophy Autosomal recessive limb-girdle muscular dystrophy type 2J Early-onset myopathy with fatal cardiomyopathy Myopathy, myofibrillar, 9, with early respiratory failure Hypertrophic cardiomyopathy 9
Affected status: yes
Allele origin:
maternal
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536714.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017 |
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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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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 |
Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent. | Lacaze P | NPJ genomic medicine | 2021 | PMID: 34135346 |
Amino Acid-Level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally Identified TTN-Encoded Titin Truncating Variants. | Connell PS | Circulation. Genomic and precision medicine | 2021 | PMID: 33226272 |
Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the TTN Gene. | Akhtar MM | Circulation. Heart failure | 2020 | PMID: 32964742 |
Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation. | Choi SH | JAMA | 2018 | PMID: 30535219 |
Exome sequencing-based molecular autopsy of formalin-fixed paraffin-embedded tissue after sudden death. | Bagnall RD | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28333919 |
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 |
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. | Pugh TJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24503780 |
Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. | Ceyhan-Birsoy O | Neurology | 2013 | PMID: 23975875 |
Truncations of titin causing dilated cardiomyopathy. | Herman DS | The New England journal of medicine | 2012 | PMID: 22335739 |
http://cardiodb.org/titin | - | - | - | - |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TTN | - | - | - | - |
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Text-mined citations for rs368219776 ...
HelpRecord last updated Oct 08, 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.