chr1-201364366-G-A

Position:

chr1-201364366-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_001276345.2(TNNT2):c.421C>T(p.Arg141Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,434 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 1.06

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:

ENSG00000286600 (HGNC:):

ENSG00000286600 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001276345.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-201364365-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

PP5

Variant 1-201364366-G-A is Pathogenic according to our data. Variant chr1-201364366-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201364366-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2 link	c.421C>T	p.Arg141Trp	missense_variant	11/17	ENST00000656932.1	NP_001263274.1	P45379-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1 link	c.421C>T	p.Arg141Trp	missense_variant	11/17		NM_001276345.2	ENSP00000499593.1		P45379-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460434

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726570

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:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1D

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 03, 2008	- -

Cardiovascular phenotype

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 02, 2024	The p.R131W pathogenic mutation (also known as c.391C>T), located in coding exon 9 of the TNNT2 gene, results from a C to T substitution at nucleotide position 391. The arginine at codon 131 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in multiple individuals with features consistent with dilated cardiomyopathy (DCM) and/or left ventricular non-compaction cardiomyopathy, including a de novo occurrence, and has been reported to segregate with disease in a family with DCM (Mogensen J et al. J Am Coll Cardiol. 2004;44(10):2033-40; Klaassen S et al. Circulation. 2008;117(22):2893-90; Merlo M et al. Clin Transl Sci. 2013;6(6):424-8; Pugh TJ et al. Genet Med. 2014;16(8):601-8; Bagnall RD et al. Circ Genom Precis Med. 2022 Dec;15(6):e003686; Khan RS et al. J Am Heart Assoc. 2022 Jan;11(1):e022854; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 22, 2017	Variant summary: The TNNT2 c.391C>T (p.Arg131Trp) variant results in a non-conservative amino acid substitution located in the tropomyosin binding domain of the protein (Mogensen_2004, Klaassen_2008). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/116588 control chromosomes at a frequency of 0.0000086, which does not exceed the estimated maximal expected allele frequency of a pathogenic TNNT2 variant (0.000175). This variant has been found in 4 probands (1st with DCM, 2nd with LVNC, 3rd with DCM/LVNC, and 4th with DCM) in the reported literature. In the first family, it was found to co-segregate with DCM in at least two affected members. In second family, the variant was found to be de novo in the affected proband; however, it is not specified whether paternity was confirmed. In the third family, affected mother was available for genotyping but she did not carry the variant. From the results of third family, authors assume the variant either to be VUS or disease-causing having reduced penetrance. The unaffected father in the family was not available for genotyping. Though this lack of co-segregation may indicate that it may not be pathogenic, the possibility that another familial variant was explaining the phenotype in the mother which remained untransmitted in the proband cannot be ruled out. In addition, this variant could have a reduced penetrance and could have been transmitted from the unaffected father, or it could have originated de novo. The variant has also been reported in two patients with DCM by LMM/PH (unpublished findings). Several independent functional studies dating from 2004 to 2016 have demonstrated that this variant results in a depressed myofilament calcium sensitivity in alpha-MHC (myosin heavy chains) thereby inducing a more severe DCM-like contractile phenotype against an alpha-MHC background. These results are consistent with an established molecular mechanism of disease due to an alteration in the contractile dynamics in the presence of mutations in TNNT2. Three diagnostic centers via ClinVar interpret the variant as pathogenic/likely pathogenic, without evidence for independent evaluation. There are also other potentially pathogenic missense variants around this variant (such as such as p.E128K, p.R130C and p.R134G), suggesting a notion that the region may have a functional importance. Taken all evidences together, this variant is classified as Likely Pathogenic until additional reports demonstrating unequivocal co-segregation with disease in independent families with multiple affected and unaffected members are obtained. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 04, 2022

Published functional studies demonstrate a damaging effect as this variant alters troponin protein-protein interaction and calcium affinity (Mogensen et al., 2004; Mirza et al., 2005; Robinson et al., 2007; Liu et al., 2012; Gollapudi et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32458740, 17932326, 23302633, 24503780, 24817852, 28352236, 34935411, 21551322, 24119082, 15923195, 15542288, 20973921, 25163546, 18056765, 22337857, 27181684, 26183555, 25110706, 22464770, 27757084, 18506004, 27532257, 28611029, 31918855, 33025817, 32618513, 33906374, 22675533) -

Cardiomyopathy, familial restrictive, 3

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Primary dilated cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 30, 2013

The Arg131Trp variant in TNNT2 has been identified in 1 individual with LVNC whe re it was reported to have occurred de novo (Klaassen 2008) and has now been ide ntified by our laboratory in 2 individuals with DCM. It was not identified in la rge population studies. Additionally, studies have shown that the Arg131Trp vari ant alters calcium binding properties of the thin filaments (Robinson 2007, Lui 2012). However, these in vitro assays may not accurately represent biological fu nction. Arginine (Arg) at position 131 is highly conserved in mammals and across evolutionarily distant species and the change to tryptophan (Trp) was predicted to be pathogenic using a computational tool clinically validated by our laborat ory. This tool's pathogenic prediction is estimated to be correct 94% of the tim e (Jordan 2011). In summary, this variant is likely to be pathogenic, though add itional studies are required to fully establish its clinical significance. -

Hypertrophic cardiomyopathy 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

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

Mar 14, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 131 of the TNNT2 protein (p.Arg131Trp). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 15542288, 15923195, 17932326, 22675533). 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. ClinVar contains an entry for this variant (Variation ID: 12415). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) and left ventricular non compaction (LVNC) (PMID: 15542288, 18506004, 21551322, 24119082). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

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

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.80

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.91

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

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

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-7.2

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

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.73

MutPred

0.44

.;.;.;.;Loss of methylation at R141 (P = 0.2583);.;.;.;.;.;.;Loss of methylation at R141 (P = 0.2583);

MVP

0.98

MPC

1.4

ClinPred

0.98

GERP RS

3.2

Varity_R

0.74

gMVP

0.96

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