rs267607123
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2
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
Consequence
NM_003280.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251122Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135792
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461468Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727044
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74358
ClinVar
Submissions by phenotype
not specified Uncertain:2
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). -
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
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 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. -
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Hypertrophic cardiomyopathy 13 Pathogenic:1
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not provided Uncertain:1
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Cardiovascular phenotype Uncertain:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at