NM_001276345.2:c.890G>A

Variant names:

• chr1-201359217-C-T
• rs727504247
• NM_001276345.2:c.890G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_001276345.2(TNNT2):​c.890G>A​(p.Trp297*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,610,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 2.38

Genes affected

TNNT2 (HGNC:11949): (troponin T2, cardiac type) This gene encodes the cardiac isoform of troponin T. The encoded protein is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration. Mutations in this gene have been associated with familial hypertrophic cardiomyopathy as well as with dilated cardiomyopathy. [provided by RefSeq, May 2022]

ENSG00000286600 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PP5: Variant 1-201359217-C-T is Pathogenic according to our data. Variant chr1-201359217-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201359217-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-201359217-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.890G>A	p.Trp297*	stop_gained	Exon 17 of 17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.890G>A	p.Trp297*	stop_gained	Exon 17 of 17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000413 AC: 1 AN: 242296 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130664

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1457848 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 724570

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74328

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported to segregate with disease in two families, but no details were provided (Brito et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last two amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Limited functional studies using human induced pluripotent stem cell-derived cardiomyocytes suggest that this variant impacts protein function (Pettinato et al., 2020); however additional studies are needed to validate the functional effect of this variant in vivo; This variant is associated with the following publications: (PMID: 12707239, 27532257, 20439259, 23396983, 25351510, 26936621, 22857948, 20031601, 30297972, 33025817, 30975432) -

Jan 16, 2012

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Trp287Stop (c.860 G>A, W287X) in TNNT2. Given strong case data, absence in controls, and segregation in multiple families, (all reviewed below) we consider this variant likely disease causing. The variant has been seen in at least 14 unrelated cases of HCM (not including the patient's family). There is weak segregation data in at least 6 families. Brito et al (2012) observed the variant in 3 of 77 unrelated individuals with HCM in their Portuguese cohort. Two of these patients have affected relatives and the authors note the variant segregated with disease however they do not provide details on the number of affected relatives with the variant. Richard et al (2003) observed the variant in 2 unrelated patients in their cohort of 197 HCM patients from France (likely redundant with Gandjbackhch et al 2010 from the same group). Bill McKenna's group observed the variant in 1 out of 223 HCM patients from their UK cohort (Lopes et al 2013). GeneDx shared they've seen it in one patient tested for HCM (presumably this family) and two tested with a DCM panel. I have requested phenotype and ancestry data. A genetic testing lab shared with us that they have seen the variant in multiple patients with HCM with segregation in some families. Of note, most of these cases were Portuguese. The variant affects one of the last residues in the protein, though it is a bit unclear how far to the end (the labs and papers conflict). The testing lab reports we have do not provide the transcript they used. Per another source, this affects the second last residue of the protein, creating a stop codon where there would normally be a tryptohan. It would lead to loss of the last two amino acids. Unlike nonsense variants that occur earlier in the amino acid sequence this variant would most likely not lead to nonsense-mediate mRNA decay. Notably, the end of the protein is highly conserved across mammals In total the variant has not been seen in ~6400 published controls and individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6300 Caucasian and African American individuals (as of February 18th, 2014). It is also not listed in dbSNP. The variant was not observed in 100 healthy adults analyzed by Richard et al (2003). Unfortunately there are not any Portuguese controls available. -

Oct 12, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 2 Pathogenic:3

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Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 14, 2023

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Pathogenic:2

May 12, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Pathogenic:2

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1D Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Pathogenic:1

Jun 06, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy, familial restrictive, 3 Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Apr 11, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Dec 10, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	45
DANN	Uncertain	0.99
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.49
GERP RS		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727504247; hg19: chr1-201328345;