NM_001276345.2:c.544G>T

Variant names:

• chr1-201363352-C-A
• rs730881097
• NM_001276345.2:c.544G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1 PP3_Moderate PP5 BS2

The NM_001276345.2(TNNT2):​c.544G>T​(p.Ala182Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,614,072 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:3
• 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]

ENSG00000286600 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001276345.2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875
• PP5: Variant 1-201363352-C-A is Pathogenic according to our data. Variant chr1-201363352-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181612.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=1, Likely_pathogenic=4}. Variant chr1-201363352-C-A is described in Lovd as [Pathogenic]. Variant chr1-201363352-C-A is described in Lovd as [Likely_pathogenic].
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.544G>T	p.Ala182Ser	missense_variant	Exon 12 of 17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.544G>T	p.Ala182Ser	missense_variant	Exon 12 of 17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152180 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251496 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000711 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:2

Mar 07, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala172Ser variant in TNNT2 has been reported in 1 individual with DCM and segregated with disease in at least 4 affected relatives (Stefanelli 2004). Present in ClinVar (ID 18162) and gnomad 4/282894 total chromosomes. It has also been identified in 1/80 HCM patients by Viswanathan 2017. This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala172Ser variant is uncertain. ACMG/AMP Criteria applied: PM2, PP1, PP3. -

Jul 10, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with serine at codon 172 of the TNNT2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been shown to segregate with dilated cardiomyopathy in multiple affected individuals in two families (PMID: 15464434, 35653365). This variant has also been reported in two additional unrelated individuals affected with dilated cardiomyopathy (PMID: 22292720, 28008009) and two individuals affected with hypertrophic cardiomyopathy (PMID: 29121657, 35653365). This variant has been identified in 4/282894 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiomyopathy Pathogenic:1

Jan 02, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with serine at codon 172 of the TNNT2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been shown to segregate with dilated cardiomyopathy in multiple affected individuals in two families (PMID: 15464434, 35653365). This variant has also been reported in two additional unrelated individuals affected with dilated cardiomyopathy (PMID: 22292720, 28008009) and two individuals affected with hypertrophic cardiomyopathy (PMID: 29121657, 35653365). This variant has been identified in 4/282894 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Oct 18, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A172S variant (also known as c.514G>T), located in coding exon 10 of the TNNT2 gene, results from a G to T substitution at nucleotide position 514. The alanine at codon 172 is replaced by serine, an amino acid with similar properties. This variant was identified in individuals with features consistent with dilated cardiomyopathy (DCM) and segregated with disease in at least one family (Stefanelli CB et al. Mol Genet Metab, 2004;83:188-96; Jáchymová M et al. Physiol Res, 2012 Jan;61:169-75; Dewey FE et al. Science, 2016 Dec;354:[ePub ahead of print]; Viswanathan SK et al. PLoS One, 2017 Nov;12:e0187948; Stava TT et al. Eur J Prev Cardiol, 2022 Oct;29:1789-1799; Ambry internal data; external communication). In an assay testing TNNT2 function, this variant showed a functionally abnormal result (Pettinato AM et al. Circulation, 2020 Dec;142:2262-2275). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 172 of the TNNT2 protein (p.Ala172Ser). This variant is present in population databases (rs730881097, gnomAD 0.004%). This missense change has been observed in individuals with dilated cardiomyopathy or hypertrophic cardiomyopathy (PMID: 15464434, 22292720, 29121657; internal data). It has also been observed to segregate with disease in related individuals. This variant is also known as A171S. ClinVar contains an entry for this variant (Variation ID: 181612). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TNNT2 protein function with a negative predictive value of 80%. Studies have shown that this missense change alters TNNT2 gene expression (PMID: 33025817). For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1D Uncertain:1

Oct 12, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TNNT2 c.514G>T (p.Ala172Ser) missense variant (which has also been referred to as p.Ala171Ser) has been reported in two studies in which it was identified in a heterozygous state in at least nine clinically affected members of a large, multigenerational family affected by left ventricular dilatation, systolic dysfunction, and sudden cardiac death (Stefanelli et al. 2004). The p.Ala172Ser variant was also detected in an unrelated individual with dilated cardiomyopathy (Jáchymová et al. 2012). Three clinically indeterminate and three asymptomatic members of the large family also carried the variant. Within the family, male carriers of the variant had more severe symptoms, and two of them died suddenly (Stefanelli et al. 2004). The p.Ala172Ser variant was absent from 212 control individuals and is reported at a frequency of 0.000024 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies of the variant have not been conducted, but it affects a highly conserved residue in the alpha-tropomyosin binding domain (Stefanelli et al. 2004). Based on the limited evidence available, the p.Ala172Ser variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal dominant dilated cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Cardiomyopathy, familial restrictive, 3 Uncertain:1

Oct 11, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hypertrophic cardiomyopathy 2 Uncertain:1

Oct 11, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
CardioboostCm	Uncertain	0.57
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;.;.;.;D;.;.;.;.;.;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;D;.;.;D;.
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	.;.;.;.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.2	N;N;.;.;N;.;.;.;N;N;N
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0070	D;D;.;.;D;.;.;.;D;D;D
Sift4G	Benign	0.26	T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.99, 0.99	.;.;.;.;D;.;.;.;.;.;D
Vest4		0.79
MVP		0.95
MPC		1.4
ClinPred		0.91	D
GERP RS		4.9
Varity_R		0.29
gMVP		0.65

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: rs730881097; hg19: chr1-201332480;