Submissions for variant NM_003280.3(TNNC1):c.430A>G (p.Asn144Asp)

gnomAD frequency: 0.00001  dbSNP: rs730881061

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003236784	SCV000209146	likely pathogenic	not provided	2023-06-20	criteria provided, single submitter	clinical testing	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)
Invitae	RCV000471611	SCV000550242	likely pathogenic	Dilated cardiomyopathy 1Z; Hypertrophic cardiomyopathy 13	2024-01-30	criteria provided, single submitter	clinical testing	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.
Center for Human Genetics, University of Leuven	RCV000497492	SCV000579541	pathogenic	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770185	SCV000901613	uncertain significance	Cardiomyopathy	2016-11-24	criteria provided, single submitter	clinical testing
3billion	RCV001808432	SCV002058453	likely pathogenic	Hypertrophic cardiomyopathy 13	2022-01-03	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002326908	SCV002630914	uncertain significance	Cardiovascular phenotype	2023-11-03	criteria provided, single submitter	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV003952794	SCV004774068	likely pathogenic	TNNC1-related condition	2024-01-03	criteria provided, single submitter	clinical testing	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.