rs1553651640

Positions:

• chr3-52451445-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The ENST00000232975.8(TNNC1):​c.400G>A​(p.Glu134Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E134D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNNC1 ENST00000232975.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain EF-hand 4 (size 33) in uniprot entity TNNC1_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in ENST00000232975.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNC1	NM_003280.3	c.400G>A	p.Glu134Lys	missense_variant	5/6	ENST00000232975.8	NP_003271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNC1	ENST00000232975.8	c.400G>A	p.Glu134Lys	missense_variant	5/6	1	NM_003280.3	ENSP00000232975	P1
TNNC1	ENST00000496590.1	c.268G>A	p.Glu90Lys	missense_variant	4/4	2		ENSP00000420596
TNNC1	ENST00000461086.1	n.331G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2024	Reported in individuals with DCM in published literature and referred for genetic testing at GeneDx; at least one of these individuals harbored additional cardiogenetic variants (PMID: 26899768, 36252119, 35653365, 38612618); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36252119, 26899768, 35653365, 38612618) -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 15, 2018	- -

TNNC1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2023

The TNNC1 c.400G>A variant is predicted to result in the amino acid substitution p.Glu134Lys. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 134 of the TNNC1 protein (p.Glu134Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 26899768; Invitae). ClinVar contains an entry for this variant (Variation ID: 470558). 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. This variant disrupts the p.Glu134 amino acid residue in TNNC1. Other variant(s) that disrupt this residue have been observed in individuals with TNNC1-related conditions (PMID: 18572189), which suggests that this may be a clinically significant amino acid residue. 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

The p.E134K variant (also known as c.400G>A), located in coding exon 5 of the TNNC1 gene, results from a G to A substitution at nucleotide position 400. The glutamic acid at codon 134 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in a patient with dilated cardiomyopathy (Cuenca S et al. J. Heart Lung Transplant. 2016;35:625-35). This amino acid position is well 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.070	T;.
Polyphen		0.99	D;.
Vest4		0.83
MutPred		0.55		Gain of ubiquitination at E134 (P = 0.0162);.;
MVP		0.64
MPC		1.5
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.86
gMVP		0.90

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: rs1553651640; hg19: chr3-52485461; COSMIC: COSV51767211; COSMIC: COSV51767211;