rs267607123

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PM1PP2PP3_ModerateBS2

The NM_003280.3(TNNC1):c.86T>A(p.Leu29Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,613,670 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

TNNC1
NM_003280.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:6

Conservation

PhyloP100: 3.65

Publications

50 publications found

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 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

TNNC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 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, 9 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

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BS2

High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNC1	NM_003280.3 link	c.86T>A	p.Leu29Gln	missense_variant	Exon 3 of 6	ENST00000232975.8	NP_003271.1	P63316Q6FH91

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNNC1	ENST00000232975.8 link	c.86T>A	p.Leu29Gln	missense_variant	Exon 3 of 6	1	NM_003280.3	ENSP00000232975.3	P63316
TNNC1	ENST00000496590.1 link	c.-47T>A		5_prime_UTR_variant	Exon 2 of 4	2		ENSP00000420596.1	C9JDI3
TNNC1	ENST00000461086.1 link	n.-231T>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251122

AF XY:

0.00

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 FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461468

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727044

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

53006

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Mar 11, 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.Leu29Gln variant in TNNC1 has been reported in 1 adult with HCM (Hoffmann 2001) and was absent from large population studies. Several vitro studies provid e conflicting data with some supporting a functional impact and others refuting this effect (Schmidtmann 2005, Baryshnikova 2008, Liang 2008, Dweck 2008, Neulen 2009, Parvatiyar 2012, Gollapudi 2012, Li 2013). Please note that in vitro assa ys may not accurately represent biological function. Leucine (Leu) at position 2 9 is conserved in mammals but not in evolutionarily distant species, and >10 fis h species carry a glutamine (Gln), raising the possibility that this change may be tolerated. In summary, due to the presence of conflicting data, the clinical significance of the p.Leu29Gln variant is uncertain. -

Oct 18, 2011

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. p.Leu29Gln (c.86 T>A) in TNNC1 Of note, variants in TNNC1 are very rare and there is some debate about whether the strength of the evidence implicating this gene in cardiomyopathy. The variant has been seen in at least 1 unrelated case of HCM (not including this patient's family). No segregation data is available. The variant appears to be the first one reported in TNNC1 in association with HCM (Hoffmann et al 2001). I could not access the paper, however the following summary was provided in OMIM: "In a 60-year-old German man with hypertrophic cardiomyopathy (CMH13; 613243), Hoffmann et al. (2001) identified an 86T-A transversion in exon 3 of the TNNC1 gene, leading to a leu29-to-gln (L29Q) substitution at a conserved residue. No family members were available for study. The mutation was not detected in 96 controls, but the authors stated that they could not determine whether this was a disease-causing variant." In silico analysis with polyphen2 predicts this variant to be benign. In silico analysis with MutationTaster predicts the variant to be disease causing. The Leucine at codon is not completely conserved across species, and is in fact a glutamine in some species. Very few variants have been reported in association with disease in this gene, however at least one variant in a nearby codons (p.Ala31Ser (Parvatiyar et al 2012) has been reported with cardiomyopathy. Schmidtmann et al. (2005) studied the structural and functional consequences of this variant and observed only minor effects on secondary structure by circular dichroism (CD) spectroscopy. Schmidtmann et al. (2005) concluded that the variant hinders transduction of the phosphorylation signal from cardiac TnI to cardiac TnC. Liang et al. (2008) reported that the L29Q mutation enhances the Ca2??-binding characteristics of cTnC and that when incorporated into cardiac myocytes, this mutant alters myocyte contractility. Dweck et al. (2008) found that he lack of myofilament changes from L29Q-CTnC may preserve diastolic and systolic function, but is still indicative of the clinical outcome of HCM. Neulen et al. (2009) reported that this variant is unlikely to induce development of HCM by affecting regulation of Ca2+ activated force and interference with protein kinase A mediated modulation of Ca2+ sensitivity of contraction. In total the variant has not been seen in ~64,496 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 29 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of January 21st, 2015, assuming same transcript, testing report doesn't provide transcript). The variant was not observed in the following laboratory and published control samples: 96 (Hoffmann et al 2001), 400 ethnically diverse controls studied by Familion/PGxHealth/Transgenomic. There is no variation at codon 29 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of January 21st, 2015, assuming same transcript, testing report doesn't provide transcript). -

Dilated cardiomyopathy 1Z;C2750472:Hypertrophic cardiomyopathy 13

Uncertain:2

Mar 07, 2023

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 29 of the TNNC1 protein (p.Leu29Gln). This variant is present in population databases (rs267607123, gnomAD 0.005%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 11385718, 38002985). ClinVar contains an entry for this variant (Variation ID: 12442). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TNNC1 function (PMID: 16302972, 18042489, 18063575, 18285522, 18820258, 19506933, 23008774, 23633581, 24260207, 26341255). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Hypertrophic cardiomyopathy 13

Pathogenic:1

Dec 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1

Feb 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Mar 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.L29Q variant (also known as c.86T>A), located in coding exon 3 of the TNNC1 gene, results from a T to A substitution at nucleotide position 86. The leucine at codon 29 is replaced by glutamine, an amino acid with dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Hoffmann B et al. Hum Mutat, 2001 Jun;17:524). Several functional studies were performed for this alteration; however, they provided indeterminant results (Schmidtmann A et al. FEBS J, 2005 Dec;272:6087-97; Dweck D et al. J Biol Chem, 2008 Nov;283:33119-28; Liang B et al. Physiol Genomics, 2008 Apr;33:257-66; Neulen A et al. Basic Res Cardiol, 2009 Nov;104:751-60; Gollapudi SK et al. Biochem Res Int, 2012 Sep;2012:824068; Li AY et al. PLoS One, 2013 Nov;8:e79363; Stevens CM et al. J Biol Chem, 2017 Jul;292:11915-11926; Rayani K et al. FEBS J, 2022 Dec;289:7446-7465; Tikunova SB et al. Int J Mol Sci, 2023 Aug;24:[ePub ahead of print]). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.31

Eigen

Benign

-0.13

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

-0.046

MutationAssessor

Benign

-0.070

PhyloP100

3.6

PrimateAI

Uncertain

0.75

PROVEAN

Benign

2.1

REVEL

Uncertain

0.51

Sift

Benign

0.22

Sift4G

Benign

0.14

Polyphen

0.0

Vest4

0.73

MutPred

0.81

Gain of catalytic residue at L29 (P = 0.0201);

MVP

0.95

MPC

2.0

ClinPred

0.64

GERP RS

5.8

Varity_R

0.39

gMVP

0.86

Mutation Taster

=27/73

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.91

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.91

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over