ClinVar Genomic variation as it relates to human health
NM_001267550.2(TTN):c.96235G>A (p.Asp32079Asn)
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); Benign(2); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001267550.2(TTN):c.96235G>A (p.Asp32079Asn)
Variation ID: 196196 Accession: VCV000196196.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q31.2 2: 178543909 (GRCh38) [ NCBI UCSC ] 2: 179408636 (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 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001267550.2:c.96235G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001254479.2:p.Asp32079Asn missense NM_001256850.1:c.91312G>A NP_001243779.1:p.Asp30438Asn missense NM_003319.4:c.69040G>A NP_003310.4:p.Asp23014Asn missense NM_133378.4:c.88531G>A NP_596869.4:p.Asp29511Asn missense NM_133432.3:c.69415G>A NP_597676.3:p.Asp23139Asn missense NM_133437.4:c.69616G>A NP_597681.4:p.Asp23206Asn missense NC_000002.12:g.178543909C>T NC_000002.11:g.179408636C>T NG_011618.3:g.291894G>A NG_051363.1:g.26083C>T LRG_391:g.291894G>A - Protein change
- D32079N, D30438N, D29511N, D23014N, D23206N, D23139N
- Other names
- p.D30438N:GAT>AAT
- Canonical SPDI
- NC_000002.12:178543908: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00050
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 | ||
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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
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. |
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TTN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
11831 | 31475 | |
LOC126806421 | - | - | - | GRCh38 | - | 258 |
TTN-AS1 | - | - | - | GRCh38 | - | 18025 |
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. |
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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jul 5, 2023 | RCV000219446.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV000273519.7 | |
Benign (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV000316543.7 | |
Benign (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV000334102.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV000375971.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV000388603.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 6, 2017 | RCV000464293.6 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 25, 2019 | RCV000617391.5 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Dec 8, 2023 | RCV000725268.14 | |
Likely benign (1) |
criteria provided, single submitter
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May 26, 2023 | RCV003150052.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 1, 2023 | RCV003319185.3 | |
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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
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. |
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Benign
(Jan 12, 2018)
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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: SCV000420608.3
First in ClinVar: Dec 06, 2016 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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Uncertain significance
(Jan 12, 2018)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000420612.3
First in ClinVar: Dec 06, 2016 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Benign
(Jan 12, 2018)
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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: SCV000420611.3
First in ClinVar: Dec 06, 2016 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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Uncertain significance
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Early-onset myopathy with fatal cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000420609.3
First in ClinVar: Dec 06, 2016 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2J
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000420607.3
First in ClinVar: Dec 06, 2016 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Likely benign
(Jun 08, 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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GeneDx
Accession: SCV000237820.7
First in ClinVar: Jul 05, 2015 Last updated: Jul 24, 2021 |
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Uncertain significance
(Jun 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
Affected status: yes
Allele origin:
germline
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Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University
Accession: SCV003932375.1
First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
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Likely benign
(Jul 05, 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: SCV004029881.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: TTN c.88531G>A (p.Asp29511Asn) results in a conservative amino acid change located in the A-band domain of the encoded protein sequence. Three of four … (more)
Variant summary: TTN c.88531G>A (p.Asp29511Asn) results in a conservative amino acid change located in the A-band domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.88531G>A has been reported in the literature in individuals affected with sudden unexplained death/sudden infant death syndrome or fetal loss without evidence for causality (examples: Campuzano_2015, Kline_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Co-occurrence with a pathogenic variant have been reported (TTN c.38632A>T, p.Arg12878X), providing supporting evidence for a benign role. 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: 26516846, 34756330). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as likely benign (n=2) or uncertain significance (n=6). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Dec 08, 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: SCV003827906.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely benign
(May 26, 2023)
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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
Accession: SCV003838517.2
First in ClinVar: Mar 11, 2023 Last updated: Feb 04, 2024 |
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Likely benign
(Sep 25, 2019)
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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: SCV000736061.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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)
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Uncertain significance
(Apr 06, 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: SCV000542406.2
First in ClinVar: Apr 17, 2017 Last updated: Dec 26, 2017 |
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Uncertain significance
(Sep 22, 2015)
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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: SCV000335505.3
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Mar 24, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000272810.3
First in ClinVar: May 29, 2016 Last updated: Dec 15, 2018 |
Comment:
The p.Asp29511Asn variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 12/66690 European chromosomes a nd 6/11544 … (more)
The p.Asp29511Asn variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 12/66690 European chromosomes a nd 6/11544 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs200540781). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though t his information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Asp29511Asn variant is uncertain. (less)
Number of individuals with the variant: 1
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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:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552760.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The TTN p.Asp23014Asn variant was not identified in the literature but was identified in dbSNP (ID: rs200540781), ClinVar (classified as uncertain significance by GeneDx, Invitae, … (more)
The TTN p.Asp23014Asn variant was not identified in the literature but was identified in dbSNP (ID: rs200540781), ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics, EGL Genetic Diagnostics, Laboratory for Molecular Medicine and Invitae) and LOVD 3.0 (classified as a VUS). The variant was identified in control databases in 51 of 280188 chromosomes at a frequency of 0.000182 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 15 of 35360 chromosomes (freq: 0.000424), Other in 2 of 7126 chromosomes (freq: 0.000281), European (non-Finnish) in 32 of 128056 chromosomes (freq: 0.00025) and African in 2 of 24182 chromosomes (freq: 0.000083), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Asp23014 residue has limited species conservation information and computational analyses (PolyPhen-2, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (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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Embryonic lethal genetic variants and chromosomally normal pregnancy loss. | Kline J | Fertility and sterility | 2021 | PMID: 34756330 |
Rare Titin (TTN) Variants in Diseases Associated with Sudden Cardiac Death. | Campuzano O | International journal of molecular sciences | 2015 | PMID: 26516846 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TTN | - | - | - | - |
Text-mined citations for rs200540781 ...
HelpRecord last updated Jul 29, 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.