GeneBe

rs730881097

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PP3_ModeratePP5BS2

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

Scores

10
6
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:3

Conservation

PhyloP100: 5.65
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1
In a region_of_interest Disordered (size 99) in uniprot entity TNNT2_HUMAN there are 38 pathogenic changes around while only 2 benign (95%) 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: {Likely_pathogenic=3, Uncertain_significance=3, Pathogenic=1}. 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/exons MANE Protein UniProt
TNNT2NM_001276345.2 linkuse as main transcriptc.544G>T p.Ala182Ser missense_variant 12/17 ENST00000656932.1 NP_001263274.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TNNT2ENST00000656932.1 linkuse as main transcriptc.544G>T p.Ala182Ser missense_variant 12/17 NM_001276345.2 ENSP00000499593 A2P45379-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:4Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJan 04, 2024This 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. -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 07, 2019The 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. -
Cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 02, 2024This 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. -
Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 03, 2023This 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 individual(s) with dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM) (PMID: 15464434, 22292720, 29121657). 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function. 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
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaOct 12, 2017The 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
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaOct 11, 2017This 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
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaOct 11, 2017This 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;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs730881097; hg19: chr1-201332480; API