ClinVar Genomic variation as it relates to human health
NM_133378.4(TTN):c.37385_37387delAAG
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.
Uncertain significance(8); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_133378.4(TTN):c.37385_37387delAAG
Variation ID: 202444 Accession: VCV000202444.17
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 2q31.2 2: 178621733-178621735 (GRCh38) [ NCBI UCSC ] 2: 179486460-179486462 (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 Jun 8, 2015 Feb 4, 2024 Sep 7, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001267550.2:c.45089_45091delAAG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001256850.1:c.40166_40168delAAG splice acceptor NM_003319.4:c.17894_17896delAAG NM_133378.4:c.37385_37387del NM_133378.4:c.37385_37387delAAG splice acceptor NC_000002.12:g.178621735TCT[2] NC_000002.11:g.179486462TCT[2] NG_011618.3:g.214062AAG[2] NG_051363.1:g.103909TCT[2] LRG_391:g.214062AAG[2] LRG_391t1:c.45089_45091del - Protein change
- Other names
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- Canonical SPDI
- NC_000002.12:178621732:CTTCTTCTTCT:CTTCTTCT
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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.
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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 |
11682 | 30988 | |
LOC126806427 | - | - | - | GRCh38 | - | 202 |
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
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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 (7) |
criteria provided, multiple submitters, no conflicts
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Sep 7, 2023 | RCV000184304.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 14, 2017 | RCV000473301.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 27, 2017 | RCV000584801.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV001375600.2 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 16, 2020 | RCV002399688.1 |
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
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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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Uncertain significance
(Jun 24, 2013)
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criteria provided, single submitter
Method: research
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Not provided
Affected status: unknown
Allele origin:
unknown
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000051171.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015 |
Number of individuals with the variant: 1
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Uncertain significance
(May 15, 2014)
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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: SCV000236929.2
First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
c.40166_40168delAAG: p.Glu13389del (E13389del) in exon 195 of the TTN gene (NM_001256850.1). The c.40166_40168delAAG variant has not been published as a mutation or as a benign … (more)
c.40166_40168delAAG: p.Glu13389del (E13389del) in exon 195 of the TTN gene (NM_001256850.1). The c.40166_40168delAAG variant has not been published as a mutation or as a benign polymorphism to our knowledge. c.40166_40168delAAG results in deletion of Glutamic acid at position 13389 and does not cause a shift in reading frame. Only one in-frame deletion/duplication mutation in the TTN gene has been reported in association with tibial muscular dystrophy. Furthermore, c.40166_40168delAAG is not located in the A-band region of TTN, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s). (less)
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Uncertain significance
(Dec 14, 2017)
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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
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000542390.3
First in ClinVar: Apr 17, 2017 Last updated: May 26, 2018 |
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Uncertain significance
(Sep 27, 2017)
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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: SCV000334527.3
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Uncertain significance
(Jun 03, 2019)
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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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Athena Diagnostics Inc
Accession: SCV001146408.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
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Likely benign
(Sep 16, 2020)
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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: SCV002711450.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Mar 27, 2017)
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criteria provided, single submitter
Method: research
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Arrhythmogenic right ventricular dysplasia 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV000692525.2
First in ClinVar: Feb 25, 2018 Last updated: Dec 11, 2022 |
Comment:
The TTN Glu13389del results in an in-frame deletion of a glutamine (Glu) at position 13389. We have identified this variant in a proband presenting with … (more)
The TTN Glu13389del results in an in-frame deletion of a glutamine (Glu) at position 13389. We have identified this variant in a proband presenting with sudden cardiac death, they were diagnosed with ARVC at post-mortem. The proband has no family history of disease. The variant is present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), at an allele frequency of 0.0002163, which is higher then expected for an inherited heart condition. The clinical consequence of TTN in-frame deletions are currently unknown. Therefore, we classify TTN Glu13389del as a variant of "uncertain significance" though this may be downgraded in future. (less)
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Uncertain significance
(Apr 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: SCV001572506.2
First in ClinVar: Apr 30, 2021 Last updated: Jun 03, 2023 |
Comment:
Variant summary: TTN c.37385_37387delAAG (p.Glu12462del) results in an in-frame deletion that is predicted to remove one amino acid that is located in the I-band region … (more)
Variant summary: TTN c.37385_37387delAAG (p.Glu12462del) results in an in-frame deletion that is predicted to remove one amino acid that is located in the I-band region of the encoded protein. The variant allele was found at a frequency of 0.00015 in 243276 control chromosomes, predominantly at a frequency of 0.00034 and 0.00027 within the East Asian and European subpopulations, respectively (gnomAD database). These frequencies are somewhat lower than the maximum expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (DCM) phenotype (0.00039). However, in certain European subpopulations the variant occurs with an even higher frequency, e.g. in the Swedish (allele frequency: 0.00052), suggesting that the variant might be a benign polymorphism. c.37385_37387delAAG has been reported in the literature as a VUS in settings of multigene panel testing in at-least one individual within a cohort with Pediatric Dilated Cardiomyopathy (example, Khan_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as uncertain significance (n=8) (LB, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(Sep 07, 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: SCV003827905.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001920672.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953255.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Genotype and Cardiac Outcomes in Pediatric Dilated Cardiomyopathy. | Khan RS | Journal of the American Heart Association | 2022 | PMID: 34935411 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TTN | - | - | - | - |
Text-mined citations for rs759525338 ...
HelpRecord last updated Mar 17, 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.