rs730881118

chr1-201363379-CC-AA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_001276345.2(TNNT2):c.516_517delinsTT(p.Glu172_Glu173delinsAspTer) variant causes a stop gained change. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E172E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:4
• Conservation: PhyloP100: 5.65

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2	c.516_517delinsTT	p.Glu172_Glu173delinsAspTer	stop_gained	12/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1	c.516_517delinsTT	p.Glu172_Glu173delinsAspTer	stop_gained	12/17		NM_001276345.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, flagged submission

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jan 16, 2012

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.Glu162AspfsX1 (E162DfsX1; c.486_487delGGinsTT) in the TNNT2 gene. Seen in a patient in our center with isolated heart block. To date, it is not clear that premature stop codons in the gene TNNT2 gene typically cause disease. Furthermore, this gene is not a good match to our patient's phenotype, as it is not known to cause isolated heart block. This variant is completely novel, and has not been previously reported as a disease-causing mutation or as a benign polymorphism. It appears that the TNNT2 gene has not been associated in the literature with heart block as a presenting feature in the absence of cardiomyopathy. The protein encoded by this gene 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. As described by GeneDx, mutations in TNNT2 have been reported in 5-15% of patients with autosomal dominant familial hypertrophic cardiomyopathy (HCM), often characterized by minimal left ventricular hypertrophy but a high incidence of sudden cardiac death (Moolman et al. 1997; Cirino et al. 2011). Mutations in TNNT2 have been reported less frequently in association with autosomal dominant DCM (Hershberger et al. 2009), and in some cases these patients with DCM have developed heart block. This is an in-frame alteration of 2 adjacent nucleotides that results in a change of Glutamic Acid 162 to an Aspartic Acid, and creation of a premature stop codon immediately downstream. This variant is expected to create either a truncated, abnormal protein product or loss of protein from this allele through nonsense-mediated decay. However, the vast majority of known disease-causing changes in TNNT2 are missense, indicating that haploinsufficiency of TNNT2 may not be sufficient to cause disease. HGMD contains at least one pathogenic splicing variant in TNNT2. Truncating variants do appear in population datasets. The NHLBI Exome Sequencing Project dataset currently contains 2 frameshift variants in TNNT2, and has variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 5/21/2013). One of these frameshift variants is present in 1 Caucasian individual, the other is present in 2 Caucasian individuals. dbSNP apparently contains 1 frameshift variant. Given the mismatch between this gene and our patient’s phenotype, plus the uncertain effects of TNNT2 truncating variants, it seems unlikely that this variant is the explanation for our patient’s heart block. Pathogenicity would be more likely if this variant occurred de novo in the patient or segregates with disease in the family. -

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2016

This sequence change inserts 2 nucleotides in exon 11 of the TNNT2 mRNA (c.486_487delGGinsTT), causing a frameshift at codon 163. This creates a premature translational stop signal (p.Glu162_Glu163delinsAsp*) and is expected to result in an absent or disrupted protein product. At least two truncating variants that affect the last exon of the TNNT2 gene are known to be Pathogenic (PMID: 8205619, 12707239, 20439259, 22857948, 23396983) and truncated versions TNNT2 have dominant negative effects in vitro (PMID: 10617660, 10850966). In addition, other disease-causing missense variants show decreased calcium sensitivity of force development (PMID: 20031601) which suggests that haploinsufficiency could also be a mechanism. However, haploinsufficiency has not been conclusively demonstrated as causing disease. As a result, this has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Mar 02, 2016

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 11, 2023

This sequence change creates a premature translational stop signal (p.Glu162_Glu163delinsAsp*) in the TNNT2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TNNT2 cause disease. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with TNNT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 181638). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs730881118; hg19: chr1-201332507;