The p.R136Q variant (also known as c.407G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 407. The arginine at codon 136 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (Millat G et al. Eur J Med Genet. 2010 Jul;53(5):261-7; Coto E et al. J Mol Diagn, 2012 Sep;14:518-24; T; Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Osadnik T et al. Kardiol Pol. 2022 Feb;80(4):482-484). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic for autosomal dominant TNNI3-related cardiomyopathy; however, its clinical significance for autosomal recessive TNNI3-related dilated cardiomyopathy is uncertain.
ClinVar Genomic variation as it relates to human health
NM_000363.5(TNNI3):c.407G>A (p.Arg136Gln)
Germline
Classification
Help
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.
(7)
Help
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.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(5); Uncertain significance(1)
Pathogenic(1); Likely pathogenic(5); Uncertain significance(1)
7
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000363.5(TNNI3):c.407G>A (p.Arg136Gln)
Variation ID: 181576 Accession: VCV000181576.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19q13.42 19: 55665540 (GRCh37) [ NCBI UCSC ] 19: 55154172 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 29, 2015 Sep 16, 2024 Jul 12, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000363.5:c.407G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000354.4:p.Arg136Gln missense NC_000019.10:g.55154172C>T NC_000019.9:g.55665540C>T NG_007866.2:g.8561G>A NG_011829.2:g.67G>A LRG_432:g.8561G>A LRG_432t1:c.407G>A LRG_679:g.67G>A - Protein change
- R136Q
- Other names
-
p.R136Q:CGA>CAA
- Canonical SPDI
- NC_000019.10:55154171:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| TNNI3 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
699 | 760 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 12, 2024 | RCV000159213.8 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Dec 14, 2023 | RCV000167999.12 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Nov 30, 2022 | RCV000769526.4 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Apr 24, 2020 | RCV001781500.1 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
May 10, 2024 | RCV002321670.3 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Nov 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000900921.3 First in ClinVar: May 06, 2019 Last updated: Feb 04, 2024 |
|
|
|
Likely pathogenic
(May 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002626501.3
First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024 |
Comment:
The p.R136Q variant (also known as c.407G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide … (more)
The p.R136Q variant (also known as c.407G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 407. The arginine at codon 136 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (Millat G et al. Eur J Med Genet. 2010 Jul;53(5):261-7; Coto E et al. J Mol Diagn, 2012 Sep;14:518-24; T; Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Osadnik T et al. Kardiol Pol. 2022 Feb;80(4):482-484). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic for autosomal dominant TNNI3-related cardiomyopathy; however, its clinical significance for autosomal recessive TNNI3-related dilated cardiomyopathy is uncertain. (less)
|
|
|
Likely pathogenic
(Apr 24, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 7
Affected status: unknown
Allele origin:
germline
|
New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002025676.1 First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
Comment:
The c.407G>A, p.Arg136Gln variant has 0.0004% allele frequency in the gnomAD database (1 out of 248,592 heterozygous alleles), indicating this is a rare allele. This … (more)
The c.407G>A, p.Arg136Gln variant has 0.0004% allele frequency in the gnomAD database (1 out of 248,592 heterozygous alleles), indicating this is a rare allele. This sequence change has been observed in individuals affected with hypertrophic cardiomyopathy [PMID: 28356264; PMID:27532257; PMID: 24510615; PMID: 22765922; PMID: 20624503]. In silico tools(SIFT, PolyPhen-2, Align-GVGD, REVEL, and CADD) suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Based on available evidence this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Autistic behavior (present) , Ptosis (present) , Delayed speech and language development (present)
Secondary finding: yes
|
|
|
Uncertain Significance
(Dec 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004838446.1
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)
|
Comment:
This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 20624503, 20800588, 24510615, 24793961, 25132132, 27532257, 30297972, 35176171). This variant is located in … (more)
This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 20624503, 20800588, 24510615, 24793961, 25132132, 27532257, 30297972, 35176171). This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described (PMID: 20624503). This variant is present in 1/248592 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). (less)
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Jan 08, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000928159.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019
Comment:
Patient analyzed with Hypertrophic Cardiomyopathy (HCM) Panel
|
|
|
|
Pathogenic
(Sep 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000218650.9
First in ClinVar: Mar 29, 2015 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 181576). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 20624503, 22765922, 24510615, 27532257, 28356264; Invitae). This variant is present in population databases (rs730881069, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 136 of the TNNI3 protein (p.Arg136Gln). (less)
|
|
|
Likely pathogenic
(Jul 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000209159.13
First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis indicates that … (more)
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23140321, 27532257, 20624503, 22765922, 24510615, 34426522, 33336002, 33193569, 33087929, 37652022, 25132132, 38880420, 30297972, 35176171, 24793961, 20800588) (less)
|
Comment:
Comment:
The c.407G>A, p.Arg136Gln variant has 0.0004% allele frequency in the gnomAD database (1 out of 248,592 heterozygous alleles), indicating this is a rare allele. This sequence change has been observed in individuals affected with hypertrophic cardiomyopathy [PMID: 28356264; PMID:27532257; PMID: 24510615; PMID: 22765922; PMID: 20624503]. In silico tools(SIFT, PolyPhen-2, Align-GVGD, REVEL, and CADD) suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Based on available evidence this variant has been classified as Likely Pathogenic.
Comment:
This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 20624503, 20800588, 24510615, 24793961, 25132132, 27532257, 30297972, 35176171). This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described (PMID: 20624503). This variant is present in 1/248592 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 181576). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 20624503, 22765922, 24510615, 27532257, 28356264; Invitae). This variant is present in population databases (rs730881069, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 136 of the TNNI3 protein (p.Arg136Gln).
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23140321, 27532257, 20624503, 22765922, 24510615, 34426522, 33336002, 33193569, 33087929, 37652022, 25132132, 38880420, 30297972, 35176171, 24793961, 20800588)
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. |
Comment:
The p.R136Q variant (also known as c.407G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 407. The arginine at codon 136 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (Millat G et al. Eur J Med Genet. 2010 Jul;53(5):261-7; Coto E et al. J Mol Diagn, 2012 Sep;14:518-24; T; Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Osadnik T et al. Kardiol Pol. 2022 Feb;80(4):482-484). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic for autosomal dominant TNNI3-related cardiomyopathy; however, its clinical significance for autosomal recessive TNNI3-related dilated cardiomyopathy is uncertain.
Comment:
The c.407G>A, p.Arg136Gln variant has 0.0004% allele frequency in the gnomAD database (1 out of 248,592 heterozygous alleles), indicating this is a rare allele. This sequence change has been observed in individuals affected with hypertrophic cardiomyopathy [PMID: 28356264; PMID:27532257; PMID: 24510615; PMID: 22765922; PMID: 20624503]. In silico tools(SIFT, PolyPhen-2, Align-GVGD, REVEL, and CADD) suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Based on available evidence this variant has been classified as Likely Pathogenic.
Comment:
This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 20624503, 20800588, 24510615, 24793961, 25132132, 27532257, 30297972, 35176171). This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described (PMID: 20624503). This variant is present in 1/248592 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 181576). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 20624503, 22765922, 24510615, 27532257, 28356264; Invitae). This variant is present in population databases (rs730881069, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 136 of the TNNI3 protein (p.Arg136Gln).
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23140321, 27532257, 20624503, 22765922, 24510615, 34426522, 33336002, 33193569, 33087929, 37652022, 25132132, 38880420, 30297972, 35176171, 24793961, 20800588)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genotype-phenotype correlations in Polish patients with hypertrophic cardiomyopathy: Preliminary report. | Osadnik T | Kardiologia polska | 2022 | PMID: 35176171 |
| Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). | Ho CY | Circulation | 2018 | PMID: 30297972 |
| Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients. | Gómez J | Circulation. Cardiovascular genetics | 2017 | PMID: 28356264 |
| 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 |
| Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy. | Wang J | European journal of heart failure | 2014 | PMID: 25132132 |
| Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy. | Bos JM | Mayo Clinic proceedings | 2014 | PMID: 24793961 |
| Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise. | Kapplinger JD | Journal of cardiovascular translational research | 2014 | PMID: 24510615 |
| Resequencing the whole MYH7 gene (including the intronic, promoter, and 3' UTR sequences) in hypertrophic cardiomyopathy. | Coto E | The Journal of molecular diagnostics : JMD | 2012 | PMID: 22765922 |
| Development of a high resolution melting method for the detection of genetic variations in hypertrophic cardiomyopathy. | Millat G | Clinica chimica acta; international journal of clinical chemistry | 2010 | PMID: 20800588 |
| Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy. | Millat G | European journal of medical genetics | 2010 | PMID: 20624503 |
Text-mined citations for rs730881069 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 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.