rs730881097

chr1-201363352-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP3_ModeratePP5

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

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]

TNNT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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, 9 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=3}. Variant chr1-201363352-C-A is described in Lovd as [Pathogenic]. Variant chr1-201363352-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2 linkuse as main transcript	c.544G>T	p.Ala182Ser	missense_variant	12/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1 linkuse as main transcript	c.544G>T	p.Ala182Ser	missense_variant	12/17		NM_001276345.2	A2	P45379-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

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:

AN:

251496

Hom.:

AF XY:

0.00000736

AC XY:

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:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

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:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

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.:

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 submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 04, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 07, 2019	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. -

Cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 02, 2024

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. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 03, 2023

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 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 submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 12, 2017

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 (JÃ¡chymovÃ¡ 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 submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 11, 2017

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 11, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

CardioboostCm

Uncertain

0.57

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.87

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.69

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over