chr3-52451410-G-T

Variant names:

• chr3-52451410-G-T
• rs267607124
• NM_003280.3:c.435C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PM1 PP2 PP3_Moderate BS1_Supporting BS2

The NM_003280.3(TNNC1):​c.435C>A​(p.Asp145Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,614,066 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D145H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: TNNC1 NM_003280.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:2 U:9
• Conservation: PhyloP100: -0.766
• Publications: 40 publications found

Genes affected

TNNC1 (HGNC:11943): (troponin C1, slow skeletal and cardiac type) Troponin is a central regulatory protein of striated muscle contraction, and together with tropomyosin, is located on the actin filament. Troponin consists of 3 subunits: TnI, which is the inhibitor of actomyosin ATPase; TnT, which contains the binding site for tropomyosin; and TnC, the protein encoded by this gene. The binding of calcium to TnC abolishes the inhibitory action of TnI, thus allowing the interaction of actin with myosin, the hydrolysis of ATP, and the generation of tension. Mutations in this gene are associated with cardiomyopathy dilated type 1Z. [provided by RefSeq, Oct 2008]

TNNC1 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1Z

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 13

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 uncertain in NM_003280.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.7682 (below the threshold of 3.09). Trascript score misZ: 2.6866 (below the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy 13, dilated cardiomyopathy 1Z, familial isolated dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000723 (11/152214) while in subpopulation NFE AF = 0.000147 (10/68036). AF 95% confidence interval is 0.0000791. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNC1	NM_003280.3	c.435C>A	p.Asp145Glu	missense_variant	Exon 5 of 6	ENST00000232975.8	NP_003271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNC1	ENST00000232975.8	c.435C>A	p.Asp145Glu	missense_variant	Exon 5 of 6	1	NM_003280.3	ENSP00000232975.3
TNNC1	ENST00000496590.1	c.*5C>A		downstream_gene_variant		2		ENSP00000420596.1
TNNC1	ENST00000461086.1	n.*29C>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000132 AC: 33 AN: 250846 AF XY: 0.000133

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 FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000698 AC: 102 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.0000688 AC XY: 50 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000836 AC: 93 AN: 1111988

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000327

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Feb 21, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as compound heterozygous with other TNNC1 missense variants in two sets of siblings with severe early onset cardiomyopathy; however, the heterozygous relatives were unaffected (PMID: 27604170, 32038292); Reported multiple times in association with cardiomyopathy; however, some of these individuals harbored additional cardiogenetic variants (PMID: 18572189, 20215591, 36788754, 21056975, 27604170); 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 (PMID: 21056975, 20459070, 19439414, 21832052); This variant is associated with the following publications: (PMID: 20459070, 26232335, 28798025, 28518168, 19439414, 21832052, 22815480, 28473771, 28530094, 29253866, 32038292, 35626289, 36346469, 28049727, 24744096, 27301361, 20215591, 18572189, 36788754, 21056975, 27604170) -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TNNC1: PS3:Moderate, PP3 -

Apr 08, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2

Jun 23, 2015

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: 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. -

Feb 20, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Dilated cardiomyopathy 1Z;C2750472:Hypertrophic cardiomyopathy 13 Uncertain:2

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Sep 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1S Pathogenic:1

May 01, 2016

Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 13 Pathogenic:1

Aug 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiomyopathy Uncertain:1

Dec 22, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Jul 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	4.9
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		-0.77
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.020	D
Polyphen		0.93	P
Vest4		0.85
MutPred		0.89		Gain of solvent accessibility (P = 0.1014);
MVP		0.95
MPC		1.4
ClinPred		0.58	D
GERP RS		-3.0
Varity_R		0.87
gMVP		0.81
Mutation Taster		=7/93	disease causing

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

Other links and lift over

dbSNP: rs267607124; hg19: chr3-52485426;