ClinVar Genomic variation as it relates to human health
NM_000363.5(TNNI3):c.244C>T (p.Pro82Ser)
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
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NM_000363.5(TNNI3):c.244C>T (p.Pro82Ser)
Variation ID: 12421 Accession: VCV000012421.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.42 19: 55156239 (GRCh38) [ NCBI UCSC ] 19: 55667607 (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, 2016 May 1, 2024 Jan 31, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000363.5:c.244C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000354.4:p.Pro82Ser missense NC_000019.10:g.55156239G>A NC_000019.9:g.55667607G>A NG_007866.2:g.6494C>T LRG_432:g.6494C>T LRG_432t1:c.244C>T P19429:p.Pro82Ser - Protein change
- P82S
- Other names
- p.P82S:CCG>TCG
- Canonical SPDI
- NC_000019.10:55156238:G:A
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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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0.00459 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00145
Exome Aggregation Consortium (ExAC) 0.00169
1000 Genomes Project 0.00459
1000 Genomes Project 30x 0.00531
Trans-Omics for Precision Medicine (TOPMed) 0.00694
The Genome Aggregation Database (gnomAD) 0.00699
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
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. |
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TNNI3 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
695 | 755 |
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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Likely benign (2) |
criteria provided, single submitter
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Apr 5, 2018 | RCV000013233.38 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 7, 2019 | RCV000238609.14 | |
Benign (1) |
criteria provided, single submitter
|
Jun 25, 2015 | RCV000252511.11 | |
Likely benign (1) |
criteria provided, single submitter
|
Jun 14, 2016 | RCV000271700.13 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2024 | RCV000229361.24 | |
Likely benign (1) |
criteria provided, single submitter
|
Jun 14, 2016 | RCV000367372.13 | |
Benign/Likely benign (7) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2020 | RCV000224174.23 | |
Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
|
May 26, 2014 | RCV000036277.28 | |
Benign (1) |
criteria provided, single submitter
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Jun 3, 2019 | RCV000852767.9 | |
Likely benign (1) |
criteria provided, single submitter
|
Apr 5, 2018 | RCV001133540.12 | |
Likely benign (1) |
criteria provided, single submitter
|
Apr 5, 2018 | RCV001135028.12 | |
Likely benign (1) |
criteria provided, single submitter
|
Jun 14, 2016 | RCV000277490.13 | |
Benign (1) |
criteria provided, single submitter
|
Apr 18, 2022 | RCV002482859.8 | |
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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
(Aug 09, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696594.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
Comment:
Variant Summary: The c.244C>T variant involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a deleterious outcome. The variant was observed … (more)
Variant Summary: The c.244C>T variant involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.17%, predominantly observed in the African subpopulation at a frequency of 2.3% including 3 homozygous occurrences. This frequency exceeds the maximal expected allele frequency for a pathogenic variant in TNNI3 (0.0125%), suggesting this is a benign polymorphism found primarily in population(s) of African origin. The variant has been reported in the literature in HCM patients and controls, mostly of African descent. However, mouse model studies have suggested the variant to be a disease-modifying factor for dysfunction and adverse remodeling with aging and chronic pressure overload (Ramirez-Correa_2015), although the relationship of this finding to a monogenic causation is unclear, therefore the evidence is not weighed in its classification. Multiple reputable clinical labs have classified the variant as benign. Taken together, this variant is classified as Benign. (less)
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Likely benign
(Jan 31, 2020)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001471798.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Benign
(Dec 13, 2018)
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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: SCV000169016.11
First in ClinVar: Jun 23, 2014 Last updated: Oct 02, 2016 |
Comment:
This variant is associated with the following publications: (PMID: 23299917, 22995991, 25324519, 20981092, 18175163, 23967088, 11815426, 27150586, 21310275, 27532831, 26332594, 31006259)
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Benign
(Jan 11, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000280723.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
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Likely benign
(-)
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criteria provided, single submitter
Method: clinical testing
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NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000303833.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Likely benign
(Jun 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
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Dilated Cardiomyopathy, Recessive
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000414758.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000414759.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial Restrictive Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000414756.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000414757.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Benign
(May 26, 2014)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000230914.5
First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Benign
(Feb 09, 2012)
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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: SCV000059929.6
First in ClinVar: May 03, 2013 Last updated: May 03, 2018 |
Comment:
Pro82Ser in exon 5 of TNNI3: This variant is classified as benign based on its h igh frequency in the general population (dbSNP rs77615401; NHLBI … (more)
Pro82Ser in exon 5 of TNNI3: This variant is classified as benign based on its h igh frequency in the general population (dbSNP rs77615401; NHLBI Exome Sequencin g Project, http://evs.gs.washington.edu/EVS). A=57/G=2853 (less)
Number of individuals with the variant: 40
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Benign
(-)
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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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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987343.1
First in ClinVar: Sep 06, 2019 Last updated: Sep 06, 2019 |
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Benign
(Jun 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Hereditary transthyretin amyloidosis
Affected status: yes
Allele origin:
germline
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Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995485.1
First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019 |
Number of individuals with the variant: 2
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Likely benign
(Apr 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 7
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001294794.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Apr 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy, familial restrictive, 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001294793.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Apr 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 2A
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001293244.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Mar 07, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333212.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Benign
(Mar 19, 2018)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001350457.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
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Likely benign
(Oct 30, 2015)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
unknown
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000296906.3
First in ClinVar: Jul 31, 2016 Last updated: Dec 24, 2022 |
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Benign
(Apr 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy, familial restrictive, 1
Dilated cardiomyopathy 2A Dilated cardiomyopathy 1FF Hypertrophic cardiomyopathy 7
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002796561.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000284653.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
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Benign
(Jun 25, 2015)
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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: SCV000319864.7
First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as 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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risk factor
(Jul 01, 2008)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 7, MODIFIER OF
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033480.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 20, 2018 |
Comment on evidence:
Niimura et al. (2002) reported an individual with late-onset hypertrophic cardiomyopathy (CMH7; 613690) in whom they found a missense mutation in the TNNI3 gene. The … (more)
Niimura et al. (2002) reported an individual with late-onset hypertrophic cardiomyopathy (CMH7; 613690) in whom they found a missense mutation in the TNNI3 gene. The individual concerned had no family history of hypertrophic cardiomyopathy. The mutation, a C-to-T transition in exon 5, replaced proline with serine at amino acid position 82 (P82S). Proline-82 is highly conserved in mammalian, avian, and amphibian troponin I molecules. In a 32-year-old African American woman with severe hypertrophic cardiomyopathy and a family history of CMH and sudden cardiac death, Frazier et al. (2008) identified a heterozygous P82S mutation in the TNNI3 gene and a heterozygous missense mutation in the MYH7 gene (160760.0043). Her affected 8-year-old daughter carried only the heterozygous MYH7 mutation, whereas her as yet unaffected 13-year-old son carried only the TNNI3 P82S variant. Frazier et al. (2008) suggested that the P82S variant, which they found in 3% of healthy African Americans, is a disease-modifying mutation in severely affected individuals, and that carriers of the variant might be at increased risk of late-onset cardiac hypertrophy. (less)
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001797733.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742484.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001921672.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931510.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001967717.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 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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Diagnostic disparity and identification of two TNNI3 gene mutations, one novel and one arising de novo, in South African patients with restrictive cardiomyopathy and focal ventricular hypertrophy. | Mouton JM | Cardiovascular journal of Africa | 2015 | PMID: 25940119 |
Cardiac troponin I Pro82Ser variant induces diastolic dysfunction, blunts β-adrenergic response, and impairs myofilament cooperativity. | Ramirez-Correa GA | Journal of applied physiology (Bethesda, Md. : 1985) | 2015 | PMID: 25324519 |
Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise. | Kapplinger JD | Journal of cardiovascular translational research | 2014 | PMID: 24510615 |
An in silico analysis of troponin I mutations in hypertrophic cardiomyopathy of Indian origin. | Ramachandran G | PloS one | 2013 | PMID: 23967088 |
Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy. | Jordan DM | American journal of human genetics | 2011 | PMID: 21310275 |
Familial hypertrophic cardiomyopathy associated with cardiac beta-myosin heavy chain and troponin I mutations. | Frazier A | Pediatric cardiology | 2008 | PMID: 18175163 |
Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy. | Mogensen J | Journal of the American College of Cardiology | 2004 | PMID: 15607392 |
Cellular and molecular aspects of familial hypertrophic cardiomyopathy caused by mutations in the cardiac troponin I gene. | Gomes AV | Molecular and cellular biochemistry | 2004 | PMID: 15524171 |
Prevalence and spectrum of thin filament mutations in an outpatient referral population with hypertrophic cardiomyopathy. | Van Driest SL | Circulation | 2003 | PMID: 12860912 |
Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. | Niimura H | Circulation | 2002 | PMID: 11815426 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TNNI3 | - | - | - | - |
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Text-mined citations for rs77615401 ...
HelpRecord last updated Jun 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.