rs727504331

chr1-201365242-A-Cchr1-201365242-A-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1 PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001276345.2(TNNT2):c.360T>G(p.Phe120Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F120V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 0.363

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PS1: Transcript NM_001276345.2 (TNNT2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 235064
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr1-201365244-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 12412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant 1-201365242-A-C is Pathogenic according to our data. Variant chr1-201365242-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201365242-A-C is described in Lovd as [Pathogenic]. Variant chr1-201365242-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2	c.360T>G	p.Phe120Leu	missense_variant	10/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1	c.360T>G	p.Phe120Leu	missense_variant	10/17		NM_001276345.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251494 Hom.: 0 AF XY: 0.00 AC XY: 0 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: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 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: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 08, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2018	The F110L variant that is likely pathogenic in the TNNT2 gene has previously been reported in association with HCM and was found to segregate with HCM in at least three affected relatives from one family (Torricelli et al., 2003; Girolami et al., 2006; Olivotto et al., 2008; Coppini et al., 2014). Of note, a different nucleotide change resulting in the same amino acid substitution (c.328 T>C, p.F110L) has also been reported, and some publications only describe the variant at the protein level and do not specify the nucleotide substitution. The F110L (c.330 T>G) is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although the F110L variant is a conservative amino acid substitution, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, a different likely pathogenic missense variants at the same residue (F110I) has also been reported in association with HCM (Watkins et al., 1995; Anan et al., 1998; Yanaga et al., 1999; Konno et al., 2005). -

Hypertrophic cardiomyopathy Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 08, 2013	proposed classification - variant undergoing re-assessment, contact laboratory -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 18, 2023	This missense variant replaces phenylalanine with leucine at codon 110 in the tropomyosin binding domain 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 reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 14636924, 23074333, 27532257, 29875424, 23074333, 27532257, 29875424, 35514357). It has been shown that this variant segregates with disease in 3 affected individuals in one family (PMID: 14636924, 16858239, 18533079). This variant has also been reported in an individual affected with hypertrophic cardiomyopathy and left ventricular systolic dysfunction who also carried a pathogenic variant in the MYBPC3 gene (PMID: 32228044). This variant has been identified in 2/251494 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Phe110Ile, is considered to be disease-causing (ClinVar variation ID: 12412), suggesting that phenylalanine at this position is important for TNNT2 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Dilated cardiomyopathy 1D Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 27, 2023

This missense variant replaces phenylalanine with leucine at codon 110 in the tropomyosin binding domain 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 reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 14636924, 23074333, 27532257, 29875424, 23074333, 27532257, 29875424, 35514357). It has been shown that this variant segregates with disease in 3 affected individuals in one family (PMID: 14636924, 16858239, 18533079). This variant has also been reported in an individual affected with hypertrophic cardiomyopathy and left ventricular systolic dysfunction who also carried a pathogenic variant in the MYBPC3 gene (PMID: 32228044). This variant has been identified in 2/251494 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Phe110Ile, is considered to be disease-causing (ClinVar variation ID: 12412), suggesting that phenylalanine at this position is important for TNNT2 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hypertrophic cardiomyopathy;C0043202:Wolff-Parkinson-White pattern Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Feb 09, 2018

TNNT2 Phe110Leu had been previously identified in multiple HCM probands (Walsh R, et al., 2017; Coppini R, et al., 2014; GeneDx, Pers. Comm.) and in one family it was found to segregate to two affected family members (Torricelli F, et al., 2003). We identified this variant in 1 HCM proband and an affected parent. The proband also harbours a second mutation MYBPC3 p.Gly531Arg. The TNNT2 Phe110Leu variant is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tools SIFT, PolyPhen-2 and MutationTaster predict that this variant is deleterious. In summary, the variant has been reported in numerous cases, it is very rare in the general population, in silico tools predict the variant to impact protein function and the variant has segregated with disease in one family, therefore we classify TNNT2 Phe110Leu as 'Likely Pathogenic'. -

Cardiomyopathy, familial restrictive, 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jul 24, 2017

- -

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

Invitae

Jan 21, 2024

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 110 of the TNNT2 protein (p.Phe110Leu). This variant is present in population databases (rs727504331, gnomAD 0.004%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 14636924, 25524337). ClinVar contains an entry for this variant (Variation ID: 177807). 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%. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 33025817). This variant disrupts the p.Phe110 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9714088, 16115869, 33025817). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.0043
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.7	D;D;.;.;.;.;.;D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;D;D;D
Sift4G	Benign	0.065	T;T;T;T;T;D;T;T;.;D
Polyphen		1.0, 1.0	.;.;.;D;.;.;.;.;D;.
Vest4		0.91
MutPred		0.39		.;.;.;Loss of methylation at K125 (P = 0.0775);.;.;.;.;.;Loss of methylation at K125 (P = 0.0775);
MVP		0.93
MPC		1.5
ClinPred		1.0	D
GERP RS		-3.8
Varity_R		0.81
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs727504331; hg19: chr1-201334370;