rs121964857

chr1-201359245-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 5P and 5B. PM1 PM5 PP5 BP4 BS2

The NM_001276345.2(TNNT2):c.862C>T(p.Arg288Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000513 in 1,611,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R288H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:19
• Conservation: PhyloP100: 0.770

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001276345.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-201359244-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 177635.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1, Pathogenic=1}.
• PP5: Variant 1-201359245-G-A is Pathogenic according to our data. Variant chr1-201359245-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12411.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=17, Likely_pathogenic=3, Pathogenic=1}. Variant chr1-201359245-G-A is described in Lovd as [Pathogenic]. Variant chr1-201359245-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.1970368). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2	c.862C>T	p.Arg288Cys	missense_variant	17/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1	c.862C>T	p.Arg288Cys	missense_variant	17/17		NM_001276345.2	A2

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000360 AC: 88 AN: 244204 Hom.: 0 AF XY: 0.000425 AC XY: 56 AN XY: 131712

Gnomad AFR exome AF: 0.000255

Gnomad AMR exome AF: 0.000265

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000143

Gnomad NFE exome AF: 0.000626

Gnomad OTH exome AF: 0.000504

GnomAD4 exome AF: 0.000523 AC: 763 AN: 1459038 Hom.: 0 Cov.: 31 AF XY: 0.000505 AC XY: 366 AN XY: 725306

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000338

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.0000751

Gnomad4 NFE exome AF: 0.000642

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000421 AC: 64 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.000431 AC XY: 32 AN XY: 74332

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000661

Gnomad4 OTH AF: 0.000958

Alfa AF: 0.000638 Hom.: 0

Bravo AF: 0.000416

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000354 AC: 43

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:19

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:5

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	TNNT2: PM5, PP1, PP4, PS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2023	Published functional studies suggest this variant may alter normal calcium sensitivity and force contractility, however it is not clear how well these studies reproduce in vivo conditions in humans (Yanaga et al., 1999; Szezesna et al., 2000; Hernandez et al., 2005); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16199542, 33025817, 20038417, 25637381, 33148509, 14636924, 7898523, 23074333, 15958377, 10617660, 30847666, 31737537, 31980526, 32731933, 32290750, 31513939, 24418317, 22500102, 21846512, 27022107, 24055113, 21683708, 23299917, 22857948, 12881443, 12860912, 27930701, 26774798, 26914223, 27483260, 26681313, 28518168, 29121657, 17101185, 28193612, 25524337, 11432788, 19033660, 24503780, 26743238, 10405326, 14563299, 16777946, 20800588, 20624503, 20031618, 16715312, 19150014, 10610467, 10085122, 30762279, 31028938, 31006259, 31019283, 27600940, 25611685, 25668678, 25351510, 22144547, 21511876, 18533079, 26183555, 21310275, 20031602, 30645170, 31323898, 30972196, 34426522, 24704860, 35626289, 26507537, 16115869, 15246915, 28255936, 34008892, 28771489, 35514357, 36293497, 35441061, 34088630, 12974739, 36698941, 35679367, Pisklova2023, 37180798, 2946667, 24793961, 36264615, 23283745, 37029482, Shafaattalab2023, 34400558, Cao2023) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 29, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 21, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 16, 2022	One variant of uncertain significance, c.832C>T; p.Arg278Cys, was detected in the TNNT2 gene by massively parallel sequencing and confirmed by Sanger sequencing. The p.Arg278Cys variant (rs121964857) has been extensively reported in association with hypertrophic cardiomyopathy (HCM; first reported in Watkins 1995). However, the exact contribution of this variant to the development of HCM is currently under debate. For example, this variant is listed in the ClinVar database with conflicting interpretations of pathogenicity (Variation ID: 12411), with multiple clinical labs noting incomplete segregation/penetrance of this variants in familial studies (Garcia-Castro 2003, Theopistou 2004, Gimeno 2009, Ripoll-Vera 2016), and that multiple patients analyzed have additional clinically relevant variants in other HCM-related genes; an observation that has as has also been reported in the literature (Gimeno 2009 and Garcia-Castro 2009). Additionally, this variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish Europeans of 0.06% (identified in 76 out of 125,670 chromosomes). However, this relatively high population frequency, while disqualifying this variant as a high penetrance, early onset disease allele, would be consistent with a late onset/low penetrance model of disease etiology (see case report in Elliott 1999 for example of late onset disease in a carrier). Functional studies using isolated muscle fibers show subtle, but reproducible, changes in force generation caused by the p.Arg278Cys variant (Yanaga 199, Szczesna 2000, and Hernandez 2005). However, whether these defects in vitro are relevant to disease manifestation in human patients is not completely understood. Taken together, the clinical significance of the p.Arg278Cys variant cannot be determined with certainty. And at most, the genetic evidence is consistent with this variant being a low penetrance risk factor or genetic modifier of more penetrant alleles. References: Elliott et al. Late-onset hypertrophic cardiomyopathy caused by a mutation in the cardiac troponin T gene. N Engl J Med. 1999; 341(24): 1855-1856. PMID: 10610467. Hernandez et al. F110I and R278C troponin T mutations that cause familial hypertrophic cardiomyopathy affect muscle contraction in transgenic mice and reconstituted human cardiac fibers. J Biol Chem. 2005; 280(44): 37183-37194. PMID: 16115869. Garcia-Castro et al. Hypertrophic cardiomyopathy: low frequency of mutations in the beta-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) genes among Spanish patients. Clin Chem. 2003; 49(8): 1279-1285. PMID: 12881443 Garcia-Castro et al. Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy. Rev Esp Cardiol. 2009; 62(1): 48-56. PMID: 19150014 Gimeno et al. Hypertrophic cardiomyopathy. A study of the troponin-T gene in 127 Spanish families. Rev Esp Cardiol. 2009; 62(12): 1473-1477. PMID: 20038417 Ripoll-Vera et al. Clinical and Prognostic Profiles of Cardiomyopathies Caused by Mutations in the Troponin T Gene. Rev Esp Cardiol (Engl Ed). 2016; 69(2): 149-158. PMID: 26507537 Szczesna et al. Altered regulation of cardiac muscle contraction by troponin T mutations that cause familial hypertrophic cardiomyopathy. J Biol Chem. 2000; 275(1): 624-630. PMID: 10617660 Theopistou et al. Clinical features of hypertrophic cardiomyopathy caused by an Arg278Cys missense mutation in the cardiac troponin T gene. Am J Cardiol. 2004; 94(2): 246-249. PMID: 15246915 Watkins et al. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med. 1995; 332(16): 1058-1064. PMID: 7898523 Yanaga et al. Ca2+ sensitization and potentiation of the maximum level of myofibrillar ATPase activity caused by mutations of troponin T found in familial hypertrophic cardiomyopathy. J Biol Chem. 1999; 274(13): 8806-8812. PMID: 10085122 -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Dilated cardiomyopathy 1D Pathogenic:1 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 06, 2021	PM5, PP2, PP3, PP5 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -

Hypertrophic cardiomyopathy 2 Pathogenic:1 Uncertain:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 22, 1999	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 11, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 278 of the TNNT2 protein (p.Arg278Cys). This variant is present in population databases (rs121964857, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 7898523, 15958377, 25524337, 26507537). This variant is also known as c.862C>T (p.Arg288Cys). ClinVar contains an entry for this variant (Variation ID: 12411). 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: 10085122, 10405326, 10617660, 11432788, 16115869, 16777946, 19033660, 21683708, 22500102, 24418317). This variant disrupts the p.Arg278 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12974739, 15958377, 20057144, 23283745, 24793961). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jan 23, 2023	The inherited heterozygous c.832C>T p.(Arg278Cys) variant in TNNT2 has previously been reported in multiple individuals affected with hypertrophic cardiomyopathy and/or dilated cardiomyopathy [PMID: 7898523, 10610467, 12860912, 14636924, 15246915, 16199542, 16715312, 20031618, 25611685,30645170, 33148509, 21846512, 24503780], though a subset of those individuals also carried a variant in MYH7 and/or MYBPC3 genes that may explain their cardiac phenotype [PMID: 20038417, 20031618, 26507537, 19150014]. There are also multiple familial studies in which this variant didn’t not co-segregate with disease and exhibited reduced penetrance [PMID:26507537, 15958377, 7898523, 20038417, 19150014, 32731933]. The c.832C>T variant has been deposited in ClinVar [ClinVarID: 12411] with conflicting interpretations of pathogenicity; Pathogenic (1 entry), Likely pathogenic (6 entries), and Uncertain significance (16 entries). The c.832C>Tvariant is observed in 219 alleles (0.00037 minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8). The c.832C>T variant is located in the last exon of this 16-exon gene and is predicted to replace a moderately conserved arginine amino acid with cysteine at position 278in the alpha tropomyosin and actin-binding domain of the encoded protein [PMID:20624503]. Functional studies have revealed conflicting results about potential pathogenicity of this variant [PMID:10405326, 10085122, 10617660, 11432788, 21683708, 22500102, 24418317, 33148509]. Given the lack of compelling evidence for its pathogenicity, this inherited c.832C>T p.(Arg278Cys) variant identified in TNNT2 is classified as a Variant of UncertainSignificance. -

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 27, 2023	The p.Arg278Cys variant in TNNT2 has been reported in >30 individuals with clinical features of HCM and segregated with disease in at least 5 affected individuals (including one affected obligate carrier) from multiple families (Watkins 1995 PMID: 7898523, Elliott 1999 PMID: 10610467, Garcia-Castro 2003 PMID: 12881443, Torricelli 2003 PMID: 14636924, Van Driest 2003 PMID: 12860912, Theopistou 2004 PMID: 15246915, Ingles 2005 PMID: 16199542, Zeller 2006 PMID: 16715312, Kaski 2009 PMID: 20031618, Gimeno 2009 PMID: 20038417, Millat 2010 PMID: 20624503, Brito 2012 PMID: 22857948, Rubattu 2016 PMID: 27483260, LMM data). This variant has been identified by our laboratory in several individuals with HCM, though approximately half of them carried a second clinically significant variant in another gene. Many affected individuals carrying the p.Arg278Cys variant present at age 50 or older, suggesting a milder effect (LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 12411) and has been identified in 0.066% (45/68030) European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. Experimental studies evaluating the functional impact of this variant are conflicting: Animal models have shown that this variant does not cause significant hypertrophy or ventricular fibrosis even after chronic exercise challenge, and no difference in either ATPase calcium sensitivity or contractile force in muscle fibers ex vivo and in vitro (Hernandez 2005 PMID: 16115869), while in vitro functional studies show that this variant increases Ca2+ sensitivity and leads to abnormal myosin cross-bridges (Morimoto 1999 PMID 10405326, Yanaga 1999 PMID 10085122, Szczesna 2000 PMID 10617660, Schuldt 2021 PMID 33148509). Computational prediction tools do not provide evidence for or against an impact to the protein. In summary, while there is suspicion of a pathogenic role, likely with a milder effect when present in isolation, the clinical significance of this variant is uncertain. This variant should be interpreted carefully in the context of the individual’s age at onset. The ACMG/AMP Criteria applied: PS4_Supporting, PP1_Moderate, BP5. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 19, 2019	Variant summary: TThe variant, TNNT2 c.832C>T (p.Arg278Cys) 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 0.00035 in 271138 control chromosomes, predominantly at a frequency of 0.0006 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TNNT2 causing Hypertrophic Cardiomyopathy with Sudden Cardiac Death phenotype (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, these occurrences do need to be cautiously considered due to the cohort harboring individuals that could have a TNNT2 phenotype. The variant has been reported to cause a high risk of sudden death even in cases without HCM, and has been found in patients with a family history of sudden death, both early and late in life (Miliou_2005, Gruner_2011, Brito_2012, Theopsitou_2004, Millat_2011, and Elliot_1999). In the literature, this variant has been found to co-occur with other variants that may explain the phenotype or confer a modifying affect (MYH7 c.2782G>A, MYH7 c.2167C>T, MYBPC3 c.1505G>A, MYBPC3 c.2198G>A, MYBPC3 c.1828G>C). While there are many published studies finding the variant in HCM patients, most do not screen multiple genes or report co-occurrence information, and thus the presence of another variant causing the phenotype cannot be ruled out. In addition, many family studies indicate the variant does not cosegregate with disease and/or has low penetrance (Ripoll-Soler_2017, Gimeno_2009, Garcio-Castro_2009). Functional studies have reported the variant to lead to increased Ca2+ sensitivity of ATP in rabbit cardiac myofibrils (Yanaga_1999) but not for skinned preparations from transgenic mouse hearts (Hernandez_2005). In addition, although transgenic mice carrying the variant neither exhibited extensive ventricular fibrosis nor developed significant hypertrophy (Hernandez_2005), they did exhibit significant impairment due to diastolic function (Sirenko_2006). While these functional studies may suggest the variant plays a role in muscle function, the biological relevance of these studies for humans is unclear. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant with conflicting classifications, three times as likely pathogenic/pathogenic and four times as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance at this time. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	May 23, 2013	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. p.Arg278Cys in TNNT2 This variant was recently reviewed in detail for one of our research projects. Based on the presence in the general population and the fact that many cases carry an additional pathogenic variant, we would consider this variant a variant of uncertain significance, possibly a modifier. TNNT2 gene p.Arg278Cys (c.832C>T) Summary: -Seen in at least 51 presumably unrelated cases of HCM (26 published, >25 unpublished). -most had European ancestry (at least 30 out of 51); ancestry for others was not reported. -Also seen in DCM cases. -14 of 47 cases who had sequencing of at least MYH7 and TNNT2 had another variant. -5/14 are likely pathogenic/pathogenic, while 4/14 are VUS; 5/14 variant details were not available to confirm the classifications. -60-year-old European (Spain) female with HCM had additional variant in MYBPC3 gene (p.Arg733His) (ClinVar: VUS by GeneDx) -50-year-old European (Spain) female with HCM (LVWT of 22 mm) and her 2 affected family members carried additional variant in MYH7 (p.Asp928Asn) (ClinVar: likely pathogenic by LMM; pathogenic by GeneDx) -14-year-old European (France) individual carried a second variant in MYBPC3 (p.Asp610His) (ClinVar: VUS by LMM) -30.5-year-old HCM case (LVWT of 24 mm) had an additional variant in MYBPC3 (p.Asp560Thrfs*19) (classified as likely pathogenic by LMM) -49-year-old female of unreported ancestry with HCM (LVWT of 35) had an additional variant in MYBPC3 (p.Arg1781His) (ClinVar: VUS by LMM) -46.5-year-old European (Italy) proband with HCM (LVWT of 28 mm) and one affected family member carried a second variant in MYBPC3 gene (p.Thr1095Met) (ClinVar: not found; likely pathogenic by Florence). -56-year-old European (Italy) proband with HCM (LVWT of 18 mm) carried a second variant in MYBPC3 (p.Lys814del) (ClinVar: not found; pathogenic by Florence) -34-year-old female of unreported ancestry with HCM carried an additional variant in the MYBPC3 gene (IVS11-9G>A; c.927-9G>A) (Helms et al (2014): pathogenic based on splice site functional studies) -15-year-old of unreported ancestry with HCM (LVWT of 38) carried an additional variant in the in MYBPC3 gene (p.Ala848Gly) (ClinVar: VUS by GeneDx) -There is some segregation data. In three families, four affected relatives (in addition to probands) carried this variant and one had SCD. In two other families, four affected relatives (in addition to probands) carried p.Arg278Cys in addition to another variant. -In total, the variant has been seen in 40 of ~48,482 individuals (0.08%) from published controls and publicly available datasets that approximate the general population. Most were European ancestry (33 out of 28,255 individuals). In ExAC the highest MAF was 0.06% (33/26987 Europeans). Published cases: Watkins et al (1995) first reported the variant in a 17-year-old female who had normal left ventricular thickness yet had suffered a cardiac arrest; she was resuscitated. The ethnicity of the proband was not reported. Probands included 16 from Europe, 4 from North America, 3 from Japan, and 1 each from China, Southeast Asia, and Pakistan. While this one case is somewhat concerning for an increased risk of sudden death conferred by this variant, other reported cases have had more typical HCM courses, consistent with the marked variable expressivity often seen in primary cardiomyopathies. Elliott et al (1999) reported the variant in a 57-year-old male of unreported ancestry with HCM who was treated at St. George’s Hospital Medical School, London. The genes analyzed were not reported. The proband presented with syncope and dyspnea at the age of 54 years, and was found to have a septum of 12 mm, -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 18, 2023	This missense variant replaces arginine with cysteine at codon 278 of the TNNT2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant increases Ca2+ sensitivity and leads to abnormal myosin cross-bridges (PMID: 10085122, 10405326, 10617660, 11432788, 21683708, 22500102, 24418317, 33148509). However, these results were not reproduced in transgenic mice, which did not show Ca2+ sensitivity, ventricular fibrosis or significant hypertrophy (PMID: 19033660, 16115869, 16777946). This variant has been reported in over 30 individuals affected with hypertrophic cardiomyopathy (PMID: 7898523, 10610467, 12860912, 14636924, 15246915, 15958377, 16199542, 16715312, 20031618, 25611685, 26507537, 30645170, 30762279, 32815737, 35514357, 37431535). Four of these patients also carried pathogenic variants in MYBPC3 and MYH7, respectively (PMID: 26507537, 37431535). Segregation analysis in families has yielded inconclusive results (PMID: 14563299, 15958377, 25524337). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 21846512, 24503780) and arrhythmia (PMID: 26743238). This variant has been identified in over 200 individuals in the UK Biobank; of these individuals, four were affected with heart failure and one was affected with hypertrophic cardiomyopathy, while the majority of individuals were unaffected (PMID: 36264615). This variant has been identified in 98/275570 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, although this variant has been reported in many individuals affected with cardiovascular disorders, clinical significance of this variant is not clear due to inconclusive segregation analysis, co-occurrence with other disease-causing variants, elevated allele frequency in the general population and conflicting experimental data. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jul 20, 2017

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2024

The p.R278C variant (also known as c.832C>T), located in coding exon 15 of the TNNT2 gene, results from a C to T substitution at nucleotide position 832. The arginine at codon 278 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in many individuals with hypertrophic cardiomyopathy (HCM) and has segregated with disease in multiple small families, though it has also been detected in unaffected relatives (e.g., Watkins H et al N Engl J Med. 1995;332:1058-1064; Theopistou A et al. Am. J. Cardiol. 2004;94:246-9; Brito D et al. Rev Port Cardiol 2012;31:577-587; García-Castro M et al. Clin Chem. 2003;49:1279-1285; Alfares AA et al. Genet. Med. 2015;17:880-8; Ripoll- Vera T et al. Rev Esp Cardiol 2016;69(2):149-58). This alteration was also identified in an individual with dilated cardiomyopathy (DCM), but clinical details were limited (Millat G et al. Eur J Med Genet. 2011;54:e570-e575). Variants in other cardiac-related genes have co-occurred with this variant in a number of individuals, at least some of whom exhibited a severe HCM phenotype (Gimeno JR et al. Rev Esp Cardiol. 2009;62:1473-7; Millat G et al. Eur J Med Genet. 2010;53:261-7; Ripoll- Vera T et al. Rev Esp Cardiol 2016;69(2):149-58; Cecconi M et al. Int. J. Mol. Med. 2016;38:1111-24; Sanchez O et al. PLoS ONE. 2016;11:e0167358). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). However, this alteration is enriched in HCM cohorts compared with the general population (Alfares AA et al. Genet. Med. 2015;17:880-8; Ambry internal data). Functional studies have suggested that this alteration may affect muscle contraction, through decreased maximal force, increased Ca2+ sensitivity, and/or altered myosin cross-bridges, but the physiological relevance of these experimental results is unclear (Yanaga F et al, J Biol Chem 1999;274:8806-8812; Morimoto S et al. Biochem Biophys Res Commun. 1999;261:79-82; Szczesna D. J Biol Chem. 2000;275:624-630; Midde K et al. J Mol Cell Cardiol. 2011;51:409-418; Brunet NM et al J. Biomed. Biotechnol. 2012:657523; Hernandez OM et al. J. Biol. Chem. 2005;280:37183-94). Internal structural analysis suggests that this variant disrupts protein-protein interactions within the Troponin complex (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, it may represent a milder allele that presents with later onset and incomplete penetrance. -

Costello syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Aug 28, 2013

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Hypertrophic cardiomyopathy 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Sep 10, 2014

This TNNT2 Arg278Cys variant has been described in multiple HCM cohorts (see references) and in genetic screening of one DCM cohort (Millat G. et al., 2011). Segregation with disease has been shown where familial screening was available, though incomplete disease penetrance was observed (Gimeno JR, et al., 2009; García-Castro M, et al., 2007; Miliou A. et al., 2005; Theopistou A. et al., 2004; Watkins H, et al. 1995). The disease phenotype is variable. This mutation has been characterised by late-onset disease with mild hypertrophy but with a high incidence of sudden death. However, severe disease presentation including cardiac arrest events have been reported in young patients (Miliou A. et al., 2005; Theopistou A. et al., 2004; Watkins H. et al., 1995), including one paediatric HCM case (Kaski JP. et al., 2009). It should be noted that genetic analysis of the majority of these studies was limited to a small number of genes, and that additional mutations in other disease causing genes cannot be excluded in these patients. Studies by Gimeno JR. et al (2009) and Kaski JP. et al (2009) report carriers of the TNNT2 Arg278Cys mutation who also have a secondary mutation in another sarcomere gene present with moderate to severe phenotypes. Transgenic mouse models of this mutation did not develop significant hypertrophy or fibrosis (Hernandez OM. et al., (2005), however in vitro functional assays indicate that the mutation affects muscle contraction (Takahashi-Yanaga F. et al., 2001; Morimoto S. et al., 1999). We have detected this variant in 3 unrelated families in our cohort, though 2 families carry an additional "likely pathogenic" or "pathogenic variant" in another known HCM causing gene. Based on the current literature and our data, this variant in isolation may cause a mild phenotype, however further evidence is required to fully establish its role in disease pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
CardioboostCm	Uncertain	0.14
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.34	N
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.11	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.1	N;N;.;.;.;.;.;.;N;N
REVEL	Uncertain	0.63
Sift	Benign	0.062	T;T;.;.;.;.;.;.;D;T
Sift4G	Uncertain	0.025	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.;.;.;.
Vest4		0.52
MVP		0.92
MPC		1.7
ClinPred		0.13	T
GERP RS		3.0
Varity_R		0.30
gMVP		0.50

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

Other links and lift over

dbSNP: rs121964857; hg19: chr1-201328373;