rs730881061
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP5BS2
The NM_003280.3(TNNC1):c.430A>G(p.Asn144Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N144S) has been classified 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNC1 | NM_003280.3 | c.430A>G | p.Asn144Asp | missense_variant | 5/6 | ENST00000232975.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNC1 | ENST00000232975.8 | c.430A>G | p.Asn144Asp | missense_variant | 5/6 | 1 | NM_003280.3 | P1 | |
TNNC1 | ENST00000496590.1 | c.298A>G | p.Ter100= | incomplete_terminal_codon_variant, coding_sequence_variant | 4/4 | 2 | |||
TNNC1 | ENST00000461086.1 | downstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461848Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727226
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
TNNC1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 03, 2024 | The TNNC1 c.430A>G variant is predicted to result in the amino acid substitution p.Asn144Asp. This variant has been reported in multiple individuals with hypertrophic or dilated cardiomyopathy or heart failure (Table S1, Lopes et al. 2014. PubMed ID: 25351510; Robyns et al. 2017. PubMed ID: 29255176; Lu et al. 2018. PubMed ID: 30165862; Table S1, Robyns et al. 2019. PubMed ID: 31513939; File S2, van Lint et al. 2019. PubMed ID: 30847666; Table S2, Magrì et al. 2020. PubMed ID: 32481709; Table S4, Verdonschot et al. 2020. PubMed ID: 32880476). In one family this variant was found to segregate with hypertrophic cardiomyopathy in three individuals (Robyns et al. 2017. PubMed ID: 29255176). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has conflicting interpretations of pathogenicity, including uncertain, likely pathogenic, and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/181567/). This variant is interpreted as likely pathogenic. - |
Dilated cardiomyopathy 1Z;C2750472:Hypertrophic cardiomyopathy 13 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 144 of the TNNC1 protein (p.Asn144Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 29255176, 30165862, 30847666, 31513939, 32880476). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181567). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Hypertrophic cardiomyopathy 13 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TNNC1 related disorder (PMID:30165862, PS1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.867, PP3_P). A missense variant is a common mechanism associated with Cardiomyopathy (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Patient's phenotype is considered compatible with Cardiomyopathy, hypertrophic, 13 (3billion dataset, PP4_P). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 20, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 181567; ClinVar); This variant is associated with the following publications: (PMID: 25351510, 30165862, 32880476, 30847666, 31513939, 29255176) - |
Hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, University of Leuven | Oct 31, 2018 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 24, 2016 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 03, 2023 | The p.N144D variant (also known as c.430A>G), located in coding exon 5 of the TNNC1 gene, results from an A to G substitution at nucleotide position 430. The asparagine at codon 144 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was detected in the heterozygous state in multiple individuals with hypertrophic cardiomyopathy, including three affected members of the same family (Robyns T et al. Eur J Hum Genet, 2017 12;25:1313-1323; Robyns T et al. Eur J Med Genet. 2020 Mar;63(3):103754). This variant has also been detected in other cardiomyopathy genetic testing cohorts; however, clinical details were limited, and additional cardiac variants were detected in some cases (Lopes LR et al. Heart, 2015 Feb;101:294-301; Lu C et al. J Transl Med, 2018 08;16:241; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Magrì D et al. J Clin Med. 2020 May;9(6); Verdonschot JAJ et al. Circ Genom Precis Med. 2020 10;13(5):476-487). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at