rs727504331
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_001276345.2(TNNT2):āc.360T>Gā(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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F120V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001276345.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TNNT2 | NM_001276345.2 | c.360T>G | p.Phe120Leu | missense_variant | 10/17 | ENST00000656932.1 | NP_001263274.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TNNT2 | ENST00000656932.1 | c.360T>G | p.Phe120Leu | missense_variant | 10/17 | NM_001276345.2 | ENSP00000499593 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251494Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135922
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461888Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727246
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 09, 2023 | Segregates with HCM in at least three affected relatives from one family (PMID: 14636924); 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.; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7898523, 20031601, 16858239, 18533079, 27532257, 22144547, 33673806, 36252119, 36578016, 14636924, 25524337) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Sep 08, 2017 | - - |
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 | - - |
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 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. - |
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 | Labcorp Genetics (formerly Invitae), Labcorp | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at