ClinVar Genomic variation as it relates to human health
NM_000363.5(TNNI3):c.586G>A (p.Asp196Asn)
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.586G>A (p.Asp196Asn)
Variation ID: 12422 Accession: VCV000012422.46
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.42 19: 55151881 (GRCh38) [ NCBI UCSC ] 19: 55663249 (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, 2014 Aug 4, 2024 Sep 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000363.5:c.586G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000354.4:p.Asp196Asn missense NC_000019.10:g.55151881C>T NC_000019.9:g.55663249C>T NG_007866.2:g.10852G>A NG_011829.2:g.2358G>A LRG_432:g.10852G>A LRG_432t1:c.586G>A LRG_679:g.2358G>A P19429:p.Asp196Asn - Protein change
- D196N
- Other names
- p.D196N:GAT>AAT
- Canonical SPDI
- NC_000019.10:55151880: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
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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TNNI3 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
699 | 760 |
Conditions - Germline
Condition
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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
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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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Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 1, 2021 | RCV000013234.26 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jun 1, 2014 | RCV000148897.6 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 1, 2022 | RCV000159246.18 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 8, 2023 | RCV000461416.18 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 11, 2023 | RCV000777480.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 29, 2022 | RCV002354157.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 21, 2022 | RCV002496340.2 |
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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Likely pathogenic
(Feb 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059960.8
First in ClinVar: May 03, 2013 Last updated: May 29, 2021 |
Comment:
The p.Asp196Asn variant in TNNI3 has been reported in at least 12 individuals with HCM and segregated with disease in 3 affected individuals from 2 … (more)
The p.Asp196Asn variant in TNNI3 has been reported in at least 12 individuals with HCM and segregated with disease in 3 affected individuals from 2 families (Niimura 2002 PMID:11815426, Richard 2003 PMID:12707239, Mogensen 2004 PMID:15607392, Coppini 2014 PMID: 25524337, Berge 2014 PMID:24111713, Murphy 2016 PMID:26914223, Walsh 2017 PMID:27532257, Norrish 2019 PMID:31006259, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 12422) and has been identified in 0.002% (2/128706) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4_Strong, PP1, PM2_Supporting, PP3. (less)
Number of individuals with the variant: 10
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Likely pathogenic
(Sep 26, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 7
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001754791.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Comment:
The c.586G>A (p.Asp196Asn) variant in the TNNI3 gene has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID 11815426, 12707239, 15607392, 24111713, 25524337). This … (more)
The c.586G>A (p.Asp196Asn) variant in the TNNI3 gene has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID 11815426, 12707239, 15607392, 24111713, 25524337). This variant is observed at an ultra-low frequency in the general population (gnomAD database 2/280974) and is reported to be damaging by multiple bioinformatics algorithms. For these reasons, this variant has been classified as Likely Pathogenic. (less)
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Likely pathogenic
(May 11, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000913342.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces aspartic acid with asparagine at codon 196 in the C-terminal mobile domain of the TNNI3 protein. Computational prediction suggests that this … (more)
This missense variant replaces aspartic acid with asparagine at codon 196 in the C-terminal mobile domain of the TNNI3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 24111713, 25524337, 26914223, 27532257), and in an individual with a family history of hypertrophic cardiomyopathy (PMID: 34363016). In two unrelated families, this variant was identified in 4 of 7 family members affected with hypertrophic cardiomyopathy (PMID: 15607392). This variant has been identified in 2/280974 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Sep 08, 2023)
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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: SCV000551895.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 12422). For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict … (more)
ClinVar contains an entry for this variant (Variation ID: 12422). For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11815426, 12707239, 15607392, 24111713, 25524337, 26914223, 27532257). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs104894727, gnomAD 0.002%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 196 of the TNNI3 protein (p.Asp196Asn). (less)
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Likely pathogenic
(Jul 01, 2022)
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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: SCV002563546.14
First in ClinVar: Aug 23, 2022 Last updated: Aug 04, 2024 |
Comment:
TNNI3: PM1, PM5, PP1, PS4:Supporting
Number of individuals with the variant: 1
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Likely pathogenic
(May 01, 2021)
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criteria provided, single submitter
Method: research
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Hypertrophic cardiomyopathy 7
Affected status: unknown
Allele origin:
unknown
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Laan Lab, Human Genetics Research Group, University of Tartu
Accession: SCV002538622.1
First in ClinVar: Jul 01, 2022 Last updated: Jul 01, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Non-obstructive azoospermia (present)
Secondary finding: yes
Method: exome sequencing
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Likely pathogenic
(Apr 21, 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: SCV002811559.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Feb 10, 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: SCV000209192.15
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Mogensen et al. (2004) reported the D196N variant to be present in four affected individuals from two families with HCM; Not observed at a significant … (more)
Mogensen et al. (2004) reported the D196N variant to be present in four affected individuals from two families with HCM; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20035081, 26526134, 23299917, 25637381, 11815426, 12707239, 25524337, 24111713, 15607392, 26914223, 27532257, 28971120, 21777381, 26440512, 26199943, 31006259) (less)
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Likely pathogenic
(Sep 01, 2022)
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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: SCV004239772.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely Pathogenic
(Jul 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004819042.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant is located in the C-terminal mobile domain of the TNNI3 protein. Computational prediction tool suggests that this variant may have deleterious impact … (more)
This missense variant is located in the C-terminal mobile domain of the TNNI3 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 24111713, 25524337, 26914223, 27532257). In two unrelated families, this variant was found in 4 of 7 affected family members (PMID: 15607392). This variant has been reported in 3/277204 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different nucleotide substitution (c.586G > C) resulting in the same amino acid change has been reported in an individual affected with recessive restrictive cardiomyopathy (PMID: 30953456). Based on available evidence, this variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Dec 29, 2022)
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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: SCV002652676.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.D196N variant (also known as c.586G>A), located in coding exon 8 of the TNNI3 gene, results from a G to A substitution at nucleotide … (more)
The p.D196N variant (also known as c.586G>A), located in coding exon 8 of the TNNI3 gene, results from a G to A substitution at nucleotide position 586. The aspartic acid at codon 196 is replaced by asparagine, an amino acid with highly similar properties. This variant was identified in multiple individuals with hypertrophic cardiomyopathy (HCM) (Niimura H et al. Circulation, 2002 Jan;105:446-51; Richard P et al. Circulation, 2003 May;107:2227-32; Mogensen J et al. J. Am. Coll. Cardiol., 2004 Dec;44:2315-25; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Coppini R et al. J. Am. Coll. Cardiol., 2014 Dec;64:2589-2600; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Jan 29, 2002)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 7
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033481.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 09, 2016 |
Comment on evidence:
Niimura et al. (2002) reported an individual with late-onset hypertrophic cardiomyopathy (CMH7; 613690) in whom a missense mutation in TNNI3 was found. The individual concerned … (more)
Niimura et al. (2002) reported an individual with late-onset hypertrophic cardiomyopathy (CMH7; 613690) in whom a missense mutation in TNNI3 was found. The individual concerned had no family history of hypertrophic cardiomyopathy. The mutation, a G-to-A transition in exon 8, replaced aspartic acid with asparagine at amino acid position 196 (D196R). Aspartic acid-196 is highly conserved in mammalian, avian, and amphibian troponin I molecules. (less)
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Likely pathogenic
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Cardiomyopathy, hypertrophic
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190643.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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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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Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient management. | Kasak L | Human reproduction (Oxford, England) | 2022 | PMID: 35535697 |
Genetic testing in ambulatory cardiology clinics reveals high rate of findings with clinical management implications. | Murdock DR | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 34363016 |
Yield of Clinical Screening for Hypertrophic Cardiomyopathy in Child First-Degree Relatives. | Norrish G | Circulation | 2019 | PMID: 31006259 |
A case report of recessive restrictive cardiomyopathy caused by a novel mutation in cardiac troponin I (TNNI3). | Pantou MP | BMC medical genetics | 2019 | PMID: 30953456 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Evaluation of the Mayo Clinic Phenotype-Based Genotype Predictor Score in Patients with Clinically Diagnosed Hypertrophic Cardiomyopathy. | Murphy SL | Journal of cardiovascular translational research | 2016 | PMID: 26914223 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. | Coppini R | Journal of the American College of Cardiology | 2014 | PMID: 25524337 |
Genetics of hypertrophic cardiomyopathy in Norway. | Berge KE | Clinical genetics | 2014 | PMID: 24111713 |
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. | Andreasen C | European journal of human genetics : EJHG | 2013 | PMID: 23299917 |
Calcium-regulated conformational change in the C-terminal end segment of troponin I and its binding to tropomyosin. | Zhang Z | The FEBS journal | 2011 | PMID: 21777381 |
The C terminus of cardiac troponin I stabilizes the Ca2+-activated state of tropomyosin on actin filaments. | Galińska A | Circulation research | 2010 | PMID: 20035081 |
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 |
Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. | Richard P | Circulation | 2003 | PMID: 12707239 |
Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. | Niimura H | Circulation | 2002 | PMID: 11815426 |
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Text-mined citations for rs104894727 ...
HelpRecord last updated Aug 04, 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.