rs267607123

chr3-52452222-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP3

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:5
• Conservation: PhyloP100: 3.65

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 3 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, 7 uncertain in NM_003280.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNC1	NM_003280.3	c.86T>A	p.Leu29Gln	missense_variant	3/6	ENST00000232975.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNC1	ENST00000232975.8	c.86T>A	p.Leu29Gln	missense_variant	3/6	1	NM_003280.3	P1
TNNC1	ENST00000496590.1	c.-47T>A		5_prime_UTR_variant	2/4	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251122 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135792

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: 0.0000467

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461468 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727044

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: 0.0000189

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74358

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

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 18, 2011	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 11, 2015	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. -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 03, 2023	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). 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 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Mar 07, 2023	- -

Hypertrophic cardiomyopathy 13 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2005

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	31
Dann	Benign	0.92
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.046	T
MutationAssessor	Benign	-0.070	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	2.1	N
REVEL	Uncertain	0.51
Sift	Benign	0.22	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.73
MutPred		0.81		Gain of catalytic residue at L29 (P = 0.0201);
MVP		0.95
MPC		2.0
ClinPred		0.64	D
GERP RS		5.8
Varity_R		0.39
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs267607123; hg19: chr3-52486238;