rs267607125

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_003280.3(TNNC1):c.23C>T(p.Ala8Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000126 in 1,585,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

TNNC1
NM_003280.3 missense, splice_region

Scores

Splicing: ADA: 0.9968

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14U:1

Conservation

PhyloP100: 8.11

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.92

PP5

Variant 3-52453993-G-A is Pathogenic according to our data. Variant chr3-52453993-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-52453993-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-52453993-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNC1	NM_003280.3 link	c.23C>T	p.Ala8Val	missense_variant, splice_region_variant	1/6	ENST00000232975.8	NP_003271.1	P63316Q6FH91

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNC1	ENST00000232975.8 link	c.23C>T	p.Ala8Val	missense_variant, splice_region_variant	1/6	1	NM_003280.3	ENSP00000232975.3		P63316

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151972

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

GnomAD4 exome

AF:

0.0000133

AC:

AN:

1433628

Hom.:

Cov.:

AF XY:

0.00000985

AC XY:

AN XY:

710592

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.0000239

Gnomad4 ASJ exome

AF:

0.0000392

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000146

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151972

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74228

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:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000278

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2025	Identified in patients with hypertrophic cardiomyopathy and restrictive cardiomyopathy referred for genetic testing at GeneDx and in published literature (PMID: 27574918, 18572189, 27604170, 35769956, 28771489, 24793961, 30775854); 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: 22489623, 27604170, 33407484, 23425245, 19439414, 21056975, 20459070, 26183555, 26304555, 28473771, 28445763, 28049727, 28533433, 30138628, 30070845, 24744096, 26529187, 27721798, 34488226, 33179204, 33658040, 30847666, 35838319, 36264615, 26976709, 27574918, 28771489, 35769956, 24793961, 30775854, 18572189) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	TNNC1: PM2, PS4:Moderate, PP3, PS3:Supporting -

Hypertrophic cardiomyopathy 13

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion, Medical Genetics	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18572189). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.73; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012443). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 28, 2022	- -

Dilated cardiomyopathy 1Z;C2750472:Hypertrophic cardiomyopathy 13

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 07, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 8 of the TNNC1 protein (p.Ala8Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy and/or TNNC1-related conditions (PMID: 18572189, 27574918, 30775854, 30847666, 33658040; internal data). ClinVar contains an entry for this variant (Variation ID: 12443). 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 have shown that this missense change affects TNNC1 function (PMID: 18572189, 19439414, 20459070, 21056975, 22489623, 23425245, 26304555). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 10, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2023	Variant summary: TNNC1 c.23C>T (p.Ala8Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. As this variant is located in the exonic splice region close to the canonical intronic splice donor site, several computational tools predict a conflicting impact on normal splicing: One predicts no significant impact on splicing. One predicts the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.3e-05 in 1585600 control chromosomes (gnomAD v4.0). This frequency is not significantly higher than estimated for a pathogenic variant in TNNC1 causing Cardiomyopathy (1.3e-05 vs 2.5e-05), allowing no conclusion about variant significance. c.23C>T has been reported in the literature in individuals affected with Cardiomyopathy (eg. Landstrom_2008, Bos_2014, Jaafar_2015, Martins_2015, Ploski_2016, Jaaskelainen_2019, Mademont-Soler_2017, van Lint_2019, etc). The only segregation data reported by these studies was the observation of the variant in two siblings with infantile onset restrictive cardiomyopathy who were compound heterozygous with a second variant in TNNC1, and both heterozygous parents were asymptomatic (Ploski_2016). These data indicate that the variant is very likely to be associated with disease. There have been a variety of in vitro functional studies reported on this variant which suggest the variant impacts the function of the Troponin C protein, but the observed effects were varied and the physiological relevance of those effects in humans is unclear (eg. Landstrom_2008). Additionally, a mouse model with this variant was shown to recapitulate aspects of human HCM, further suggesting a functional impact of the variant (Martins_TNNC1_CCG_2015). The following publications have been ascertained in the context of this evaluation (PMID: 24793961, 26779504, 30775854, 18572189, 28771489, 26304555, 27604170, 30847666). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (P/LP, n=9 ; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Dilated cardiomyopathy 1Z

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 28, 2022

- -

Hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 16, 2018

proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2023

The p.A8V variant (also known as c.23C>T), located in coding exon 1 of the TNNC1 gene, results from a C to T substitution at nucleotide position 23. The alanine at codon 8 is replaced by valine, an amino acid with similar properties. This alteration has been detected in numerous individuals with hypertrophic cardiomyopathy (HCM) (Landstrom AP et al. J Mol Cell Cardiol. 2008;45:281-8; Jaafar N et al. Glob Cardiol Sci Pract. 2015;2015:16; Mademont-Soler I et al. PLoS ONE, 2017 Aug;12:e0181465; GeneDx pers. comm; Invitae pers. comm.; Ambry internal data). This alteration was also detected in siblings with early onset restrictive cardiomyopathy (RCM) who both carried a second alteration in the TNNC1 gene (Ploski R et al. Am J Med Genet A., 2016;170:3241-3248). This alteration was also reported in an infant with microcephaly and RCM (Elmas M et al. J Pediatr Genet, 2022 Jun;11:110-116). A variety of in vitro functional studies have suggested that this alteration impacts the function of the Troponin C protein, but the observed effects were varied and the physiological relevance of those effects in humans is unclear (Landstrom AP et al. J Mol Cell Cardiol. 2008;45:281-8; Pinto JR et al. J Biol Chem. 2009;284:19090-100; Swindle N et al. Biochemistry. 2010;49:4813-20; Pinto JR et al. J Biol Chem. 2011;286:1005-13; Albury AN et al. Biochemistry. 2012;51:3614-21; Cordina NM et al. Biochemistry. 2013;52:1950-62; Zot HG et al. Arch Biochem Biophys. 201;601:97-104). However, aspects of human HCM are recapitulated in a mouse model with this alteration (Martins AS et al. Circ Cardiovasc Genet. 2015;8:653-64). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jan 21, 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. p.Ala8Val (c. 23 C>T) in TNNC1 Given the lack of case data and the somewhat tenuous link between HCM and TNNC1, we classify it as a variant of uncertain significance. This variant has been reported in one individual with HCM; he was diagnosed at 33 and had no family history of SCD or HCM (Landstrom et al 2008). To the best of our knowledge there are no other published reports of this variant in HCM. There is also no segregation data available on this variant. Only a handful of variants in TNNC1 have been reported in association with HCM and some groups question whether there is sufficient evidence supporting the link between HCM and TNNC1. Interestingly, from the paper that first reported this variant we are able to get data on the prevalence of TNNC1 variants in patients with HCM, which we can then compare to the prevalence of such variants in the general population. Landstrom et al (2008) sequenced TNNC1 in 1025 patients with HCM and identified rare missense variants (including this one) in 4 individuals (i.e. ~0.4%). Of note, in a general population sample, 0.1% of individuals had a rare or unique missense variant in TNNC1 (from the NHLBI ESP data set). Landstrom et al (2008) showed that specific missense mutations occurring in TNNC1, including this p.Ala8Val variant, show increased Ca2+ sensitivity of force development and force recovery. However, a subsequent paper from the same group noted that this variant was associated with diminished Ca2+ sensitivity (Pinto et al 2009). Swindle et al (2010) reported that p.Ala8Val did not affect the calcium or magnesium binding properties of the C-domain and it had no effects on binding of troponin C to troponin I. This variant occurs in the N-helix of the amino acid-terminal domain of the protein. The Alanine at codon 8 is completely conserved (Landstrom et al 2008). PolyPhen2 predicts the variant to be possibly damaging. It is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~5,300 Caucasian and African American individuals (as of May 2012). It is also not currently listed in dbSNP or 1000 genomes (as of May 2012). Landstrom et al (2008) did not observe the variant in 500 general population samples. p. Asp464Asn (c. 1390 G>A) in PRKAG2 Genetic testing also identified another variant of unknown significance in the PRKAG2 gene, Asp464Asn (c. 1390 G>A). This variant is novel. This results in a non-conservative amino acid change, where a negatively-charged amino acid (Aspartic Acid) is changed to a neutral, polar amino acid (Asparagine). This variant is predicted to be benign by PolyPhen-2 analysis. This residue is conserved across species. No other disease-causing variants have been reported at this or nearby codons. The variant was not observed in 313 individuals of various ethnic backgrounds at GeneDx. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~5,000 Caucasian and African American individuals (as of May 2012). The variant is not listed in dbSNP or 1000 genomes (as of May 2012). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

0.39

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.46

REVEL

Pathogenic

0.73

Sift

Uncertain

0.014

Sift4G

Benign

0.17

Polyphen

0.95

Vest4

0.90

MutPred

0.78

Gain of methylation at K6 (P = 0.0501);

MVP

0.98

MPC

2.0

ClinPred

0.57

GERP RS

4.7

Varity_R

0.64

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.030

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