chr3-52451410-G-T

Position:

chr3-52451410-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 6P and 5B. PM1PM5PP3_ModerateBS1_SupportingBS2

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. D145N) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

TNNC1
NM_003280.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:9

Conservation

PhyloP100: -0.766

Variant links:

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 links:

TNNC1 (HGNC:):

TNNC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a chain Troponin C, slow skeletal and cardiac muscles (size 160) in uniprot entity TNNC1_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_003280.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-52451412-C-T is described in Lovd as [Likely_pathogenic].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. 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/exons	MANE	Protein	UniProt
TNNC1	NM_003280.3 linkuse as main transcript	c.435C>A	p.Asp145Glu	missense_variant	5/6	ENST00000232975.8	NP_003271.1	P63316Q6FH91

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TNNC1	ENST00000232975.8 linkuse as main transcript	c.435C>A	p.Asp145Glu	missense_variant	5/6	1	NM_003280.3	ENSP00000232975.3	P63316
TNNC1	ENST00000496590.1 linkuse as main transcript	c.*5C>A		downstream_gene_variant		2		ENSP00000420596.1	C9JDI3
TNNC1	ENST00000461086.1 linkuse as main transcript	n.*29C>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000132

AC:

AN:

250846

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135780

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.0000836

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000231

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2024	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	TNNC1: PS3:Moderate, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 08, 2022	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 20, 2015	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 23, 2015	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. -

Dilated cardiomyopathy 1Z;C2750472:Hypertrophic cardiomyopathy 13

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 18, 2021	- -

Dilated cardiomyopathy 1S

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

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

May 01, 2016

- -

Hypertrophic cardiomyopathy 13

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2008

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 22, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

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

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

4.9

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.77

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.10

MutationAssessor

Uncertain

2.8

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.020

Polyphen

0.93

Vest4

0.85

MutPred

0.89

Gain of solvent accessibility (P = 0.1014);

MVP

0.95

MPC

1.4

ClinPred

0.58

GERP RS

-3.0

Varity_R

0.87

gMVP

0.81

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over