rs397516482

Positions:

chr1-201361286-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_001276345.2(TNNT2):c.803A>T(p.Lys268Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,150 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 0.0000066 ( 0 hom., cov: 32)

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:4

Conservation

PhyloP100: 7.85

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a chain Troponin T, cardiac muscle (size 296) in uniprot entity TNNT2_HUMAN there are 88 pathogenic changes around while only 9 benign (91%) in NM_001276345.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.911

PP5

Variant 1-201361286-T-A is Pathogenic according to our data. Variant chr1-201361286-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43670.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=4, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2 linkuse as main transcript	c.803A>T	p.Lys268Ile	missense_variant	15/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1 linkuse as main transcript	c.803A>T	p.Lys268Ile	missense_variant	15/17		NM_001276345.2	ENSP00000499593	A2	P45379-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152150

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 17, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 19, 2023	This missense variant replaces lysine with isoleucine at codon 258 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). A functional study using human induced pluripotent stem cells has shown that this variant may impact TNNT2 protein function in manner consistent with hypertrophic cardiomyopathy (PMID: 33025817); the clinical relevance of this observation is not known. This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 26656175, 27483260, 27532257, 28640247, 29875424, 33495596, 33495597, 33673806; communication with an external laboratory; ClinVar SCV000060273.6, SCV000767829.7, SCV000209262.13). One of these individuals also carried a pathogenic variant in a different gene associated with cardiomyopathy (SCV000209262.13). 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. -

Hypertrophic cardiomyopathy

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2023	The p.Lys258Ile variant in TNNT2 has been reported in 8 individuals with hypertrophic cardiomyopathy (HCM; Bottillo 2016 PMID: 26656175, Rubattu 2016 PMID: 27483260, Walsh 2017 PMID: 27532257, Hathaway 2021 PMID: 33673806, LMM Data, Invitae Personal Communication 2023). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 43670) and has been identified in 0.0015% (1/68010) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). In vitro functional studies provide some evidence that this variant may impact protein function (Pettinato 2020 PMID: 33025817); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 26, 2023	This missense variant replaces lysine with isoleucine at codon 258 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). A functional study using human induced pluripotent stem cells has shown that this variant may impact TNNT2 protein function in manner consistent with hypertrophic cardiomyopathy (PMID: 33025817); the clinical relevance of this observation is not known. This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 26656175, 27483260, 27532257, 28640247, 29875424, 33495596, 33495597, 33673806; communication with an external laboratory; ClinVar SCV000060273.6, SCV000767829.7, SCV000209262.13). One of these individuals also carried a pathogenic variant in a different gene associated with cardiomyopathy (SCV000209262.13). 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. -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jun 26, 2017

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 258 of the TNNT2 protein (p.Lys258Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 26656175, 27483260, 27532257; Invitae). This variant is also known as c.A775T, p.Lys252Ile, c.794C>T and p.Lys265Ile. ClinVar contains an entry for this variant (Variation ID: 43670). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 30, 2024

Variant summary: TNNT2 c.773A>T (p.Lys258Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.6e-06 in 152150 control chromosomes in gnomAD database (v4.0.0). c.773A>T has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Botillo_2016, Walsh_2016, Hathaway_2021, Ho_2018, Ko_2018) with limited clinical details. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported.The following publications have been ascertained in the context of this evaluation (PMID: 26656175, 33673806, 30297972, 28640247, 27483260, 27532257). ClinVar contains an entry for this variant (Variation ID: 43670). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 09, 2017

The K258I variant in the TNNT2 gene has been published as a variant of uncertain significance in an individual with early onset HCM and a family history of disease, however no clinical details or segregation data was provided (reported as c.794 A>T, K265I, using alternate nomenclature) (Rubattu et al., 2016). It was also reported in an individual diagnosed with HCM who harbored five additional cardiogenetic variants (reported as c.755 A>T, K252I, using alternate nomenclature) (Bottillo et al., 2016). Additionally, K258I was reported as a variant of uncertain significance in two individuals in a HCM cohort, although no clinical or segregation data was provided and it is unknown if there were other co-occurring variants (Walsh et al., 2017).This variant was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server), indicating it is not a common benign variant. The K258I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties and this substitution occurs at a position that is conserved across species. Finally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Therefore, based on the currently available information, it is unclear whether the K258I variant in the TNNT2 gene is pathogenic or rare benign. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2020

The c.773A>T (p.K258I) alteration is located in exon 14 (coding exon 13) of the TNNT2 gene. This alteration results from a A to T substitution at nucleotide position 773, causing the lysine (K) at amino acid position 258 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

CardioboostCm

Uncertain

0.80

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

.;.;.;.;D;.;.;.;.;.;D

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D;D;D;D;D;D;.;.;D;.

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.91

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

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.2

.;.;.;.;M;.;.;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.9

D;D;.;.;.;.;.;.;D;D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0060

D;D;.;.;.;.;.;.;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D;D;.

Polyphen

0.99

.;.;.;.;D;.;.;.;.;.;.

Vest4

0.72

MutPred

0.46

.;.;.;.;Loss of disorder (P = 0.0045);.;.;.;.;.;.;

MVP

0.97

MPC

1.4

ClinPred

1.0

GERP RS

3.7

Varity_R

0.93

gMVP

0.90

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