1-201359216-C-T

Position:

• chr1-201359216-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001276345.2(TNNT2):​c.891G>A​(p.Trp297Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 3.10

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-201359216-C-T is Pathogenic according to our data. Variant chr1-201359216-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201359216-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2	c.891G>A	p.Trp297Ter	stop_gained	17/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1	c.891G>A	p.Trp297Ter	stop_gained	17/17		NM_001276345.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This variant changes 1 nucleotide in exon 16 of the TNNT2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 20439259; ClinVar SCV000713356.2, SCV000767821.3). Another variant resulting in the same truncation (c.890G>A, p.Trp287*) has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (ClinVar Variation ID: 177636). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 02, 2017	The p.Trp287X (c.861G>A) variant in TNNT2 has not been previously reported in th e literature or in large population studies. However, another variant (c.860G>A) that leads to the same amino acid change (p.Trp287X) has been identified in >20 individuals with HCM and segregated with disease in 7 affected relatives from 6 families (Richard 2003, Gandjbakhch 2010, Brito 2012, Lopez 2013, D. Brito pers comm, GeneDx pers comm; LMM unpublished data). Adult patients who carried this variant were noted to have mild to moderate HCM and ECG abnormalities (D. Brito pers comm). This nonsense variant leads to a premature termination codon at posi tion 287. This alteration occurs within the last exon and may therefore escape n onsense mediated decay (NMD), resulting in a truncated protein that is lacking t he last 2 amino acids. In summary, although additional studies are required to f ully establish its clinical significance, the p.Trp287X variant is likely pathog enic. ACMG/AMP Criteria applied: PS1, PM4, PM2 (Richards 2015). -

Dilated cardiomyopathy 1D Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 02, 2018

The W287X (c.861 G>A) likely pathogenic variant in the TNNT2 gene has not been reported as a pathogenic or benign to our knowledge. However, a different nucleotide change, c.860 G>A, that results in the same nonsense W287X variant, has been reported previously in several unrelated individuals diagnosed with HCM (Richard et al., 2003; Hershberger et al., 2009; Lopes et al., 2013 Brito et al., 2012; Walsh et al., 2017). The W287X variant has also been reported in individuals with HCM, but the nucleotide change was not specified (Gandjbakhch et al., 2010; Bales et al., 2016). The W287X variant is within the last exon of TNNT2 and is predicted to cause protein truncation with loss of the last two amino acid residues of the protein. Nevertheless, only one other nonsense variant in the TNNT2 gene has been reported in the Human Gene Mutation Database occurring upstream, and the clinical significance of this variant is currently unknown. Thus, in the absence of functional studies, the consequences of this variant cannot be precisely determined. Lastly, the W287X (c.861 G>A) variant is not observed in large population cohorts (Lek et al., 2016). In summary, W287X in the TNNT2 gene is interpreted as a likely pathogenic variant. -

Cardiomyopathy, familial restrictive, 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Hypertrophic cardiomyopathy 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 09, 2017

Variant summary: The TNNT2 c.861G>A (p.Trp287X) variant results in a premature termination codon, predicted to cause a truncated or absent TNNT2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs, ESP, or publications) and has been reported in multiple affected individuals. In addition, a clinical diagnostic laboratory cites the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic." -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 07, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 181636). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 22857948; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
Vest4		0.49
GERP RS		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs730881116; hg19: chr1-201328344;