Submissions for variant NM_003280.3(TNNC1):c.435C>A (p.Asp145Glu)

gnomAD frequency: 0.00010  dbSNP: rs267607124

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766925	SCV000209137	uncertain significance	not provided	2023-06-05	criteria provided, single submitter	clinical testing	Reported multiple times in association with cardiomyopathy; however, some of these individuals harbored additional cardiogenetic variants (Landstrom et al., 2008; Hershberger et al., 2010; Pinto et al., 2011a; Ploski et al., 2016; Hershberger et al., 2010; Pinto et al., 2011a; Lenarduzzi et al., 2023); Reported with another TNNC1 missense variant (p.(A8V)) in two siblings who each died in infancy from complications of severe HCM/restrictive cardiomyopathy (RCM). However, in the same study, the siblings' mother and maternal grandfather each harbored p.(D145E) in the heterozygous state and were unaffected (Ploski et al., 2016).; Published functional studies have demonstrated that p.(D145E) increases calcium sensitivity of force recovery, alters the response to protein-protein interactions within the cardiac troponin complex, and alters the response to strong cross-bridge binding (Pinto et al., 2009; Swindle et al., 2010; Pinto et al., 2011a; Pinto et al., 2011b); 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: 20459070, 26232335, 28798025, 28518168, 19439414, 21832052, 22815480, 28473771, 28530094, 29253866, 32038292, 35626289, 36346469, 36788754, 28049727, 24744096, 27301361, 20215591, 27604170, 18572189, 21056975)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000222787	SCV000272519	uncertain significance	not specified	2015-02-20	criteria provided, single submitter	clinical testing	The p.Asp145Glu variant in TNNC1 has been reported in 1 Caucasian adult with HCM (Landstrom 2008) and in 1 Caucasian adult with DCM (Pinto 2011). This variant h as been identified in 27/66086 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs2567607124). In vitro functional studies indicate this variant may lead to altered calcium sensitivity (Landstrom 2008, Swindle 2010, Pinto 2011a, Pinto 2011b); however, these types of assays may not accurately represent biological function. Computational predic tion tools and conservation analysis do not provide strong support for or agains t an impact to the protein. In summary, the clinical significance of the p.Asp14 5Glu variant is uncertain.
Invitae	RCV000227883	SCV000287938	uncertain significance	Dilated cardiomyopathy 1Z; Hypertrophic cardiomyopathy 13	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 145 of the TNNC1 protein (p.Asp145Glu). This variant is present in population databases (rs267607124, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of TNNC1-related conditions (PMID: 18572189, 21832052, 27604170, 28798025, 32038292). ClinVar contains an entry for this variant (Variation ID: 12445). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TNNC1 function (PMID: 18572189, 20459070, 21056975, 28530094, 32038292). 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.
Ambry Genetics	RCV000622135	SCV000736364	uncertain significance	Cardiovascular phenotype	2023-07-25	criteria provided, single submitter	clinical testing	The p.D145E variant (also known as c.435C>A), located in coding exon 5 of the TNNC1 gene, results from a C to A substitution at nucleotide position 435. The aspartic acid at codon 145 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been reported in one proband with hypertrophic cardiomyopathy (HCM), one proband with dilated cardiomyopathy (DCM), and one proband with left ventricular hypertrabeculation (Landstrom AP et al. J. Mol. Cell. Cardiol., 2008 Aug;45:281-8; Hershberger RE et al. Circ Cardiovasc Genet, 2010 Apr;3:155-61; Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10:[Epub ahead of print]). This variant has also been reported in at least three different families with siblings having early onset DCM or restrictive cardiomyopathy, who had additional TNNC1 variants also detected; family members who were heterozygous for only the p.D145E variant were reportedly unaffected (Ploski R et al. Am J Med Genet A, 2016 12;170:3241-3248; Klauke B et al. PLoS One, 2017 Dec;12:e0189489; Landim-Vieira M et al. Front Physiol, 2019 Jan;10:1612). Functional studies suggest this alteration may have an impact on calcium sensitivity and may have an impact on protein binding between troponin C and troponin I (Landstrom AP et al. J. Mol. Cell. Cardiol., 2008 Aug;45:281-8; Pinto JR et al. J. Biol. Chem., 2009 Jul;284:19090-100; Pinto JR et al. J. Biol. Chem., 2011 Jan;286:1005-13; Swindle N et al. Biochemistry, 2010 Jun;49:4813-20). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000227883	SCV002789500	uncertain significance	Dilated cardiomyopathy 1Z; Hypertrophic cardiomyopathy 13	2021-09-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149570	SCV003838364	uncertain significance	Cardiomyopathy	2021-12-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000766925	SCV004226122	uncertain significance	not provided	2022-04-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000766925	SCV004701721	uncertain significance	not provided	2023-12-01	criteria provided, single submitter	clinical testing	TNNC1: PS3:Moderate, PP3
OMIM	RCV000013258	SCV000033505	pathogenic	Hypertrophic cardiomyopathy 13	2008-08-01	no assertion criteria provided	literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000222787	SCV000280502	uncertain significance	not specified	2015-06-23	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. This variant has been reported in one individual with a diagnosis of HCM (Landstrom et al, 2008). No segregation analysis was performed. This variant has also been reported in one individual who was diagnosed with dilated cardiomyopathy, who also carried a second mutation in the MYBPC3 gene previously described in an HCM patient (Hershberger et al, 2010). Segregation analysis in this family was uninformative. The proband’s brother (normal cardiac screening at 63) carries the TNNC1 mutation, and the proband’s daughter (normal cardiac screening at 38 carries the MYBPC3 mutation) (Pinto et al 2009). Aspartic acid is highly conserved across species and isoforms at position 145. Polyphen predicts this variant to be “possibly damaging”. Functional studies investigating the effect of Asp145Glu on the cardiac troponin C protein confirmed an increased calcium sensitivity (first reported by Landstrom et al, 2008) and demonstrated altered calcium and magnesium binding properties of the C-terminal binding sites of troponin C and decreased affinity for interaction with troponin (Pinto et al 2009; Swindle and Tikunova 2010). We have observed a variant at the neighboring codon (p.Asn144Ser) in another family with HCM (a mother and son with HCM both have the variant). We currently consider that variant to be of unknown significance, probably disease causing. This variant was not seen in 100 African American controls and 200 Caucasian DNA samples and 200 Caucasian subjects with normal screening electro- and echocardiograms, for a total of 500 control subjects (Landstrom et al 2008). Of these controls, 400 are matched to the patient’s ethnicity. The variant is not listed in dbSNP or 1000 genomes (as of October 13, 2011). It is also not listed in the NHLBI Exome Sequencing Project dataset, which currently includes TNNC1 variant data on ~1300 European Americans and ~1050 African Americans. However, a different missense variant (p.Asp145Asn) was observed at the same codon in one of 1347 European Americans.
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen	RCV000491539	SCV000298108	likely pathogenic	Dilated cardiomyopathy 1S	2016-05-01	no assertion criteria provided	clinical testing