VCV000177636.40 - ClinVar

NM_001276345.2(TNNT2):c.890G>A (p.Trp297Ter)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Likely Pathogenic

for Hypertrophic cardiomyopathy

Classification is based on the expert panel submission

Nov 2025 by ClinGen Cardiomyopathy Variant Curation Expert Panel

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001276345.2(TNNT2):c.890G>A (p.Trp297Ter)

Variation ID: 177636 Accession: VCV000177636.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q32.1 1: 201359217 (GRCh38) [ NCBI UCSC ] 1: 201328345 (GRCh37) [ 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	Oct 11, 2015	Sep 22, 2026	Nov 14, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_001276345.2:c.890G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001263274.1:p.Trp297Ter	nonsense
NM_000364.4:c.881G>A	NP_000355.2:p.Trp294Ter	nonsense
NM_001001430.3:c.860G>A	NP_001001430.1:p.Trp287Ter	nonsense
NM_001001431.3:c.851G>A	NP_001001431.1:p.Trp284Ter	nonsense
NM_001001432.3:c.842G>A	NP_001001432.1:p.Trp281Ter	nonsense
NM_001276346.2:c.761G>A	NP_001263275.1:p.Trp254Ter	nonsense
NM_001276347.2:c.860G>A	NP_001263276.1:p.Trp287Ter	nonsense
NC_000001.11:g.201359217C>T
NC_000001.10:g.201328345C>T
NG_007556.1:g.23461G>A
LRG_431:g.23461G>A
LRG_431t1:c.890G>A	LRG_431p1:p.Trp297Ter

... more HGVS ... less HGVS

Protein change

W287*, W294*, W281*, W284*, W254*, W297*

Other names

p.W287*:TGG>TAG

Canonical SPDI

NC_000001.11:201359216:C:T

Global minor allele frequency (GMAF) Help The 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

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA005312 dbSNP: rs727504247 VarSome

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
Gene	OMIM	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.
TNNT2		No evidence available	No evidence available	GRCh38 GRCh37	1170	1193

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.
Hypertrophic cardiomyopathy 2	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 14, 2023	RCV000154218.12
not provided	Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Oct 13, 2025	RCV000159326.15
Cardiomyopathy, familial restrictive, 3 Dilated cardiomyopathy 1D Hypertrophic cardiomyopathy 2	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 18, 2026	RCV000627785.12
Hypertrophic cardiomyopathy	Likely pathogenic (3)	reviewed by expert panel	Nov 14, 2025	RCV000824774.7
Cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Jun 6, 2023	RCV001170984.4
Dilated cardiomyopathy 1D	Likely pathogenic (1)	criteria provided, single submitter	Apr 11, 2023	RCV003453151.1
Cardiovascular phenotype	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 21, 2025	RCV002444634.5
Cardiomyopathy, familial restrictive, 3	Likely pathogenic (1)	criteria provided, single submitter	Apr 11, 2023	RCV003453152.1
TNNT2-related disorder	Pathogenic (1)	criteria provided, single submitter	Aug 8, 2024	RCV006849296.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition 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.	Expand all rows Collapse all rows 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 14, 2025) C Contributing to aggregate classification	reviewed by expert panel (ClinGen CMP ACMG Specifications TNNT2 V1.0.0)	Hypertrophic cardiomyopathy (Autosomal dominant inheritance)	ClinGen Cardiomyopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV007329811.1 First in ClinVar: Jan 17, 2026 Last updated: Jan 17, 2026	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/76f96ea3-4750-4169-9a00-f6e11ea64943 Comment: show NM_001276345.2(TNNT2):c.890G>A (p.Trp297Ter). This variant has been reported in individuals with HCM (LMM data, Richard 2003 PMID: 12707239, Gandjbakhch 2010 PMID: 25575096, Brito 2012 PMID: 22857948, Lopes 2013 PMID: 23396983, Bales 2016 PMID: 26936621, Walsh 2017 PMID: 27532257, Mademont-Soler 2017 PMID: 28771489, Ho 2018 PMID: 30297972) and has been identified in been identified in 1 out of 242296 (0.002% FAF 95% CI) of global pan-ethnic chromosomes in gnomAD (PM2_Supporting; https://gnomad.broadinstitute.org/; v.2.1). This variant is statistically increased in individuals with HCM compared to controls [OR lower 95% CI >10]. Therefore, PS4_Moderate criterion has been applied. This variant segregated with disease in 7 affected relatives from 6 families (PP1_Strong; Richard 2003 PMID: 12707239, Gandjbakhch 2010 PMID: 20439259, Brito 2012 PMID: 22857948, D. Brito pers comm, GeneDx pers comm; LMM data). This nonsense variant leads to a premature termination codon at position 297. This alteration occurs within the terminal 50 bases of the last exon and is therefore likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing 2 amino acids (PM4). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner based on PS4_Moderate, PM2_Supporting, PP1_Strong and PM4. (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Pathogenic (Jun 06, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV001333647.3 First in ClinVar: May 31, 2020 Last updated: Feb 04, 2024	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Sep 14, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 2	Genomic Medicine Lab, University of California San Francisco Accession: SCV004847162.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: no Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: no

Likely pathogenic (Dec 10, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002677845.4 First in ClinVar: Nov 29, 2022 Last updated: Jan 13, 2025	Publications: PubMed (9) PubMed: 12707239‚ 20439259‚ 22857948‚ 23396983‚ 26936621‚ 27532257‚ 30297972‚ 31780822‚ 33025817 Comment: show The p.W287* variant (also known as c.860G>A), located in coding exon 15 of the TNNT2 gene, results from a G to A substitution at nucleotide position 860. This changes the amino acid from a tryptophan to a stop codon within coding exon 15. This alteration has been detected in multiple hypertrophic cardiomyopathy (HCM) cohorts and has been reported to segregate with disease, but segregation details were limited (Richard P et al. Circulation, 2003 May;107:2227-32; Brito D et al. Rev Port Cardiol, 2012 Sep;31:577-87; Lopes LR et al. J. Med. Genet., 2013 Apr;50:228-39; Bales ND et al. Pediatr Cardiol, 2016 Jun;37:845-51; Walsh R et al. Genet. Med., 2017 02;19:192-203). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). Although premature stop codons are typically deleterious in nature, loss of function of TNNT2 has not been clearly established as a mechanism of disease. This stop codon, however, occurs at the 3' terminus of TNNT2, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 2 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Feb 21, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiovascular phenotype	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000577979.2 First in ClinVar: Oct 22, 2016 Last updated: Apr 28, 2025	Comment: show PS4;PP1_strong;PVS1_mod;PM2;PP5 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Jan 18, 2026) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Cardiomyopathy, familial restrictive, 3 Hypertrophic cardiomyopathy 2 Dilated cardiomyopathy 1D Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000253859.13 First in ClinVar: Oct 11, 2015 Last updated: Feb 23, 2026	Publications: PubMed (5) PubMed: 12707239‚ 20439259‚ 22857948‚ 23396983‚ 28492532 Comment: show This sequence change creates a premature translational stop signal (p.Trp287*) in the TNNT2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acid(s) of the TNNT2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 20439259, 22857948, 23396983). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177636). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Oct 12, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502766.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (6) PubMed: 12707239‚ 20439259‚ 22857948‚ 27532257‚ 30297972‚ 33025817 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Secondary finding: no Platform type: NGS

Pathogenic (Aug 01, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 2 Dilated cardiomyopathy 1D Cardiomyopathy, familial restrictive, 3	Fulgent Genetics, Fulgent Genetics Accession: SCV002800613.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (Apr 11, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Dilated cardiomyopathy 1D	Genome-Nilou Lab Accession: SCV004180469.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Likely pathogenic (Apr 11, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy, familial restrictive, 3	Genome-Nilou Lab Accession: SCV004180470.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Likely pathogenic (Apr 11, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 2	Genome-Nilou Lab Accession: SCV004180471.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Pathogenic (May 12, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy (Autosomal dominant inheritance)	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000203872.6 First in ClinVar: Jan 31, 2015 Last updated: Apr 20, 2024	Publications: PubMed (4) PubMed: 12707239‚ 20439259‚ 22857948‚ 23396983 Comment: show The p.Trp287X variant in TNNT2 has been identified in >20 individuals with HCM and segregated with disease in 7 affected relatives from 6 families (Richard 2003 PMID: 12707239, Gandjbakhch 2010 PMID: 20439259, Brito 2012 PMID: 22857948, D. Brito pers comm, GeneDx pers comm; LMM data). Adult patients who carried this variant were noted to have mild to moderate HCM and ECG abnormalities (D. Brito pers comm). In addition, the p.Trp278X variant has been identified in 0.003% (1/32874) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 287. This alteration occurs within the last exon and may therefore escape nonsense mediated decay (NMD), resulting in a truncated protein that is lacking the last 2 amino acids. In summary, this variant meets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon case observations and segregation studies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting, PM4_Supporting. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Oct 13, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000209272.14 First in ClinVar: Feb 24, 2015 Last updated: Nov 15, 2025	Comment: show Reported to segregate with disease in two families, but no details were provided (PMID: 22857948); Identified in an infant with multiple congenital anomalies (MCA) including two-vessel cord, ventriculomegaly, a complex cardiac defect, left-right asymmetry, and dysmorphic features; this variant was maternally inherited but no clinical information was reported for the mother (PMID: 31780822); Limited functional studies using human induced pluripotent stem cell-derived cardiomyocytes suggest that this variant impacts protein function; however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 33025817); Nonsense variant predicted to result in protein truncation in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12707239, 27532257, 20439259, 23396983, 25351510, 26936621, 20031601, 30297972, 30975432, 33025817, 22857948, 31780822, 37652022, 36264615) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Oct 07, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (DASA Assertion Criteria)	not provided	Dasa Accession: SCV007669170.2 First in ClinVar: Aug 22, 2026 Last updated: Sep 13, 2026	Publications: PubMed (5) PubMed: 12707239‚ 20439259‚ 22857948‚ 27532257‚ 33025817 Comment: show NM_001276345.2(TNNT2):c.890G>A (p.Trp297Ter) is a nonsense variant in TNNT2 predicted to introduce a premature termination codon. This variant has been recurrently observed in individuals with TNNT2-related disorders (PMID: 20439259; PMID: 22857948). Segregation data support an association with disease in the reported family/families (PMID: 20439259; PMID: 22857948). Functional evidence supports an impact on the gene or gene product. Also, this variant is rare in population databases. Based on the currently available evidence, this variant is classified as likely pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (LGCM Criteria August 2015)	Hypertrophic cardiomyopathy 2 (Autosomal dominant inheritance)	Laboratory of Genetics and Molecular Cardiology, University of São Paulo Study: Sarcomeric Human Cardiomyopathy Registry (ShaRe) Accession: SCV000256206.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (1) PubMed: 12707239 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 2

Likely Pathogenic (Sep 27, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy (Autosomal dominant inheritance)	All of Us Research Program, National Institutes of Health Accession: SCV005425665.1 First in ClinVar: Dec 14, 2024 Last updated: Dec 14, 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)	Publications: PubMed (4) PubMed: 12707239‚ 20439259‚ 22857948‚ 23396983 Comment: show The c.860G>A variant in the TNNT2 gene (NM_001001430.3) is located on the last exon 16 and introduces a premature translation termination codon at 287 (p.Trp287*). The variant is located in the last exon and is not expected to result in nonsense-mediated mRNA decay. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy and segregated with disease in multiple individuals from three families (PMID: 12707239, 20439259, 22857948, 23396983). This variant has been classified as pathogenic/likely pathogenic by multiple submitters in ClinVar (ID: 177636). The variant is rare (7/1610032 chromosomes) in the general population according to gnomAD (4.1.0). Therefore, this variant has been classified as likely pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1 Zygosity: 1 Single Heterozygote

Likely pathogenic (Jan 16, 2012) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Stanford Center for Inherited Cardiovascular Disease, Stanford University Accession: SCV000280537.2 First in ClinVar: May 29, 2016 Last updated: Aug 04, 2026	Observation: 1 Collection method: provider interpretation Allele origin: germline Affected status: unknown Observation 1 Collection method: provider interpretation Allele origin: germline Affected status: unknown

Pathogenic (Aug 08, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	TNNT2-related disorders	Blueprint Genetics Accession: SCV007812079.1 First in ClinVar: Sep 22, 2026 Last updated: Sep 22, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 5 Test name: Comprehensive Cardiology Panel, Hypertrophic Cardiomyopathy (HCM) Panel

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV001928111.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Study: VKGL Data-share Consensus Accession: SCV001951833.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

NM_001276345.2(TNNT2):c.890G>A (p.Trp297Ter). This variant has been reported in individuals with HCM (LMM data, Richard 2003 PMID: 12707239, Gandjbakhch 2010 PMID: 25575096, Brito 2012 PMID: 22857948, Lopes 2013 PMID: 23396983, Bales 2016 PMID: 26936621, Walsh 2017 PMID: 27532257, Mademont-Soler 2017 PMID: 28771489, Ho 2018 PMID: 30297972) and has been identified in been identified in 1 out of 242296 (0.002% FAF 95% CI) of global pan-ethnic chromosomes in gnomAD (PM2_Supporting; https://gnomad.broadinstitute.org/; v.2.1). This variant is statistically increased in individuals with HCM compared to controls [OR lower 95% CI >10]. Therefore, PS4_Moderate criterion has been applied. This variant segregated with disease in 7 affected relatives from 6 families (PP1_Strong; Richard 2003 PMID: 12707239, Gandjbakhch 2010 PMID: 20439259, Brito 2012 PMID: 22857948, D. Brito pers comm, GeneDx pers comm; LMM data). This nonsense variant leads to a premature termination codon at position 297. This alteration occurs within the terminal 50 bases of the last exon and is therefore likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing 2 amino acids (PM4). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner based on PS4_Moderate, PM2_Supporting, PP1_Strong and PM4.

Comment:

The p.W287* variant (also known as c.860G>A), located in coding exon 15 of the TNNT2 gene, results from a G to A substitution at nucleotide position 860. This changes the amino acid from a tryptophan to a stop codon within coding exon 15. This alteration has been detected in multiple hypertrophic cardiomyopathy (HCM) cohorts and has been reported to segregate with disease, but segregation details were limited (Richard P et al. Circulation, 2003 May;107:2227-32; Brito D et al. Rev Port Cardiol, 2012 Sep;31:577-87; Lopes LR et al. J. Med. Genet., 2013 Apr;50:228-39; Bales ND et al. Pediatr Cardiol, 2016 Jun;37:845-51; Walsh R et al. Genet. Med., 2017 02;19:192-203). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). Although premature stop codons are typically deleterious in nature, loss of function of TNNT2 has not been clearly established as a mechanism of disease. This stop codon, however, occurs at the 3' terminus of TNNT2, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 2 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Trp287*) in the TNNT2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acid(s) of the TNNT2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 20439259, 22857948, 23396983). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177636). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Trp287X variant in TNNT2 has been identified in >20 individuals with HCM and segregated with disease in 7 affected relatives from 6 families (Richard 2003 PMID: 12707239, Gandjbakhch 2010 PMID: 20439259, Brito 2012 PMID: 22857948, D. Brito pers comm, GeneDx pers comm; LMM data). Adult patients who carried this variant were noted to have mild to moderate HCM and ECG abnormalities (D. Brito pers comm). In addition, the p.Trp278X variant has been identified in 0.003% (1/32874) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 287. This alteration occurs within the last exon and may therefore escape nonsense mediated decay (NMD), resulting in a truncated protein that is lacking the last 2 amino acids. In summary, this variant meets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon case observations and segregation studies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting, PM4_Supporting.

Comment:

Reported to segregate with disease in two families, but no details were provided (PMID: 22857948); Identified in an infant with multiple congenital anomalies (MCA) including two-vessel cord, ventriculomegaly, a complex cardiac defect, left-right asymmetry, and dysmorphic features; this variant was maternally inherited but no clinical information was reported for the mother (PMID: 31780822); Limited functional studies using human induced pluripotent stem cell-derived cardiomyocytes suggest that this variant impacts protein function; however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 33025817); Nonsense variant predicted to result in protein truncation in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12707239, 27532257, 20439259, 23396983, 25351510, 26936621, 20031601, 30297972, 30975432, 33025817, 22857948, 31780822, 37652022, 36264615)

Comment:

NM_001276345.2(TNNT2):c.890G>A (p.Trp297Ter) is a nonsense variant in TNNT2 predicted to introduce a premature termination codon. This variant has been recurrently observed in individuals with TNNT2-related disorders (PMID: 20439259; PMID: 22857948). Segregation data support an association with disease in the reported family/families (PMID: 20439259; PMID: 22857948). Functional evidence supports an impact on the gene or gene product. Also, this variant is rare in population databases. Based on the currently available evidence, this variant is classified as likely pathogenic.

Comment:

The c.860G>A variant in the TNNT2 gene (NM_001001430.3) is located on the last exon 16 and introduces a premature translation termination codon at 287 (p.Trp287*). The variant is located in the last exon and is not expected to result in nonsense-mediated mRNA decay. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy and segregated with disease in multiple individuals from three families (PMID: 12707239, 20439259, 22857948, 23396983). This variant has been classified as pathogenic/likely pathogenic by multiple submitters in ClinVar (ID: 177636). The variant is rare (7/1610032 chromosomes) in the general population according to gnomAD (4.1.0). Therefore, this variant has been classified as likely pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Development of a Cardiac Sarcomere Functional Genomics Platform to Enable Scalable Interrogation of Human TNNT2 Variants.	Pettinato AM	Circulation	2020	PMID: 33025817
Prospective, phenotype-driven selection of critically ill neonates for rapid exome sequencing is associated with high diagnostic yield.	Gubbels CS	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 31780822
Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe).	Ho CY	Circulation	2018	PMID: 30297972
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
Comprehensive Versus Targeted Genetic Testing in Children with Hypertrophic Cardiomyopathy.	Bales ND	Pediatric cardiology	2016	PMID: 26936621
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing.	Lopes LR	Journal of medical genetics	2013	PMID: 23396983
Sarcomeric hypertrophic cardiomyopathy: genetic profile in a Portuguese population.	Brito D	Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology	2012	PMID: 22857948
Early identification of mutation carriers in familial hypertrophic cardiomyopathy by combined echocardiography and tissue Doppler imaging.	Gandjbakhch E	European heart journal	2010	PMID: 20439259
Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy.	Richard P	Circulation	2003	PMID: 12707239
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/76f96ea3-4750-4169-9a00-f6e11ea64943	-	-	-	-

Text-mined citations for rs727504247 ...

These 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 27, 2026