Submissions for variant NM_001276345.2(TNNT2):c.418C>T (p.Arg140Cys)

gnomAD frequency: 0.00001  dbSNP: rs397516463

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036583	SCV000060238	pathogenic	Hypertrophic cardiomyopathy	2019-02-01	criteria provided, single submitter	clinical testing	The p.Arg130Cys variant in TNNT2 (ClinVar variation ID: 43636) has been reported in at least 8 families with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least 8 individuals across these families (Fujita 2013, Koga 1996, Olivotto 2008, Song 2005, Torricelli 2003, Zou 2013). This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg130Cys variant may impact protein function (Harada 2004, Gangadharan 2017). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Arg130Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon segregation studies, absence from controls, and functional evidence. ACMG/AMP criteria applied: PP1_Strong, PM2, PS4_Moderate, PP3, PS3_Supporting.
GeneDx	RCV000159290	SCV000209236	pathogenic	not provided	2022-06-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with this variant altering the contractile properties of cardiac fibers (Harada & Potter, 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23283745, 24474197, 28420666, 14722098, 23074333, 25524337, 26914223, 27532257, 28973951, 17456375, 15563892, 14636924, 30393638, 18533079, 21310275, 8951566, 30555609, 32690703, 32581830, 33025817, 23494605)
Ambry Genetics	RCV000243733	SCV000320661	likely pathogenic	Cardiovascular phenotype	2015-11-27	criteria provided, single submitter	clinical testing	The p.R130C variant (also known as c.388C>T), located in coding exon 9 of the TNNT2 gene, results from a C to T substitution at nucleotide position 388. The arginine at codon 130 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Torricelli F, Am. J. Cardiol. 2003 Dec; 92(11):1358-62. This variant was seen in a four members of a Chinese family affected with HCM (Song L, Clin. Chim. Acta 2005 Jan; 351(1-2):209-16). This variant was also reported in two adolescent Japanese siblings with HCM but also in their unaffected mother; the siblings also carried a second TNNT2 alteration that was present in their father who was affected with HCM (Fujita E, Heart Vessels 2013 Nov; 28(6):785-94). This variant was also reported to co-occur with a missense alteration in MYBPC3 in a Chinese family (Zou Y, Mol. Biol. Rep. 2013 Jun; 40(6):3969-76). In vitro studies suggest this TNNT2 p.R130C alteration may impact calcium sensitivity (Harada K, J. Biol. Chem. 2004 Apr; 279(15):14488-95). This variant was previously reported in the SNPDatabase as rs397516463. This variant was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000468121	SCV000541920	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 130 of the TNNT2 protein (p.Arg130Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 14636924, 15563892, 17456375, 23283745, 23494605, 25524337). This variant is also known as p.Arg140Cys. ClinVar contains an entry for this variant (Variation ID: 43636). 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.
Color Diagnostics, LLC DBA Color Health	RCV001187129	SCV001353814	likely pathogenic	Cardiomyopathy	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 130 in the tropomyosin binding domain 1 of the TNNT2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In vitro and in vivo functional studies in Drosophila and guinea pigs have shown that this variant impairs the function of the TNNT2 protein by causing increased calcium sensitivity, impaired relaxation and reduced cardiac output (PMID: 32581830, 32690703). This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 14636924, 15563892, 17456375, 23283745, 23494605, 25524337, 30297972, 32481709, 35514357, 36291626). This variant has been reported in the homozygous state in an individual affected with hypertrophic cardiomyopathy and no family history of cardiomyopathy (PMID: 30555609). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001187129	SCV002042848	pathogenic	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000159290	SCV002103193	pathogenic	not provided	2021-05-20	criteria provided, single submitter	clinical testing	PS3, PP1_strong, PS4_moderate, PM2_supporting, PM3_supporting, PP3
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470730	SCV002767830	pathogenic	Hypertrophic cardiomyopathy 2	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with hypertrophic cardiomyopathy 2 (MIM#115195) (PMID: 18612386). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated troponin domain (NCBI, PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in multiple individuals and families with hypertrophic cardiomyopathy 2 (MIM#115195) (ClinVar, HGMD, PMIDs: 15563892, 25524337, 28973951). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation testing). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000468121	SCV002777407	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2022-02-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450693	SCV004181419	likely pathogenic	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450694	SCV004181420	likely pathogenic	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002470730	SCV004181421	likely pathogenic	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000159290	SCV000280524	likely pathogenic	not provided	2015-05-01	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. TNNT2 variant Arg130Cys (R130C; C>T at the nucleotide level) This variant has been reported in at least 5 unrelated cases of HCM, with segregation data for at least 3 families. Koga et al. (1996) first detected it in 3 different Japanese families. The variant was “present in all affected family members” (a total of 6 people), but specific segregation data is not provided. Toricelli et al. (2003) reported Arg130Cys in an HCM patient from Tuscany with only weak segregation data: The variant was found in the proband and his affected sister. Olivotto et al. (2008) appear to be referring to that same proband. Song et al. (2005) found the variant in one Chinese family with a history of SCD, where it segregated with disease in 4 affected family members—although their degree of relationship is not reported. (Also supposedly mentioned in an abstract by Nakata et al. in 1996.) Variation at nearby loci of TNNT2 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. This includes Lys124Asn (Willott et al. 2010; Harvard Sarcomere Protein Gene Mutation Database), Arg131Trp (in DCM/LVNC; Mogensen et al. 2004), Arg131Gly (in DCM; Willott et al. 2010), Arg134Gly (in DCM; Hershberger et al. 2009; Willott et al. 2010), and Arg139His (Morales et al. 2010). This is a nonconservative amino acid change from a basic, positively-charged Arginine to a polar, neutral Cysteine (capable of forming disulfide bridges). The Arginine at codon 130 is completely conserved across 32 vertebrate species examined. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. In vitro data from Harada & Potter (2004) shows the variant to alter the contractile properties of skinned cardiac fibers. In total the variant has not been seen in ~5670 published controls and publicly available population datasets. There is no variation at codon 130 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals (as of 1/15/2012). There is no variation at this codon listed in dbSNP or 1000 genomes (as of 1/15/2012). The variant was not observed in published controls: Koga et al. (1996) did not detect Arg130Cys in more than 100 Japanese controls. Toricelli et al. (2003) did not find it in 150 healthy controls from Tuscany. Song et al. (2005) did not find it in 120 Chinese controls.