Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000154216 | SCV000203870 | likely pathogenic | Hypertrophic cardiomyopathy | 2010-07-26 | criteria provided, single submitter | clinical testing | The Ser179Phe variant in TNNT2 has been reported in one consanguineous family wi th HCM where it was present in 2 heterozygous individuals with mild HCM and in 1 homozygous individual who died early due to a severe form of HCM (Ho 2000). Thi s variant has also been identified by our laboratory in 1 adult and 1 child with HCM, and was absent from large population studies. The Ser179Phe variant was pr edicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011), which strongly supports but does not prove that the Ser1 79Phe variant is pathogenic. In summary, this variant is likely to be pathogenic and causative for HCM, though evidence suggests a milder form when present in t he heterozygous state. |
Invitae | RCV000471745 | SCV000541923 | pathogenic | Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3 | 2023-07-24 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function. ClinVar contains an entry for this variant (Variation ID: 177634). This missense change has been observed in individuals with clinical findings consistent with hypertrophic cardiomyopathy (HCM) , including a homozygous individual with severe HCM and HCM tested at a diagnostic laboratory (PMID: 11034944, 24033266, 27532257). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 179 of the TNNT2 protein (p.Ser179Phe). |
Ambry Genetics | RCV000617860 | SCV000736253 | likely pathogenic | Cardiovascular phenotype | 2023-04-26 | criteria provided, single submitter | clinical testing | The p.S179F variant (also known as c.536C>T), located in coding exon 10 of the TNNT2 gene, results from a C to T substitution at nucleotide position 536. The serine at codon 179 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was first reported in a consanguineous family with a history of hypertrophic cardiomyopathy (HCM) and sudden death. Two heterozygous individuals presented with a mild form of HCM; the variant was present in the homozygous state in an individual with a severe phenotype (Ho CY et al., Circulation 2000 Oct; 102(16):1950-5). This variant has also been detected in individuals from additional HCM cohorts or cohorts submitted for HCM genetic testing (Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Burstein DS et al. Pediatr Res. 2021 May;89(6):1470-1476). Functional studies suggest this variant may impact protein function through increased calcium sensitivity and force development; however, the physiological relevance of this finding has not been fully elucidated (Messer AE et al., Arch. Biochem. Biophys. 2016; doi: 10.1016/j.abb.2016.03.027; Harada K et al. J Biol Chem. 2004 Apr;279(15):14488-95). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 majority of the available evidence, this alteration is likely to be pathogenic. |
Broad Center for Mendelian Genomics, |
RCV001004907 | SCV001164409 | likely pathogenic | Hypertrophic cardiomyopathy 2 | 2018-12-03 | criteria provided, single submitter | research | The heterozygous p.Ser179Phe variant in TNNT2 was identified by our study in one individual with familial hypertrophic cardiomyopathy. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Ser179Phe variant in TNNT2 has been reported in 6 individuals with familial hypertrophic cardiomyopathy, segregated with disease in 6 affected relatives from a cosanguineous, two-generation family. One individual died suddenly at 17 years of age and was homozygous for the variant and the other 5 individuals were heterozygous for the variant (PMID: 11034944). This variant has been reported pathogenic and likely pathogenic in ClinVar and two individuals with this variant in the heterozygous state and with familial hypertrophic cardiomyopathy were reported in ClinVar (Variation ID: 177634). In summary, although additional studies are required to fully establish its clinical significance, the p.Ser179Phe variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PP1_Strong (Richards 2015). |
Genome- |
RCV003453149 | SCV004181302 | likely pathogenic | Dilated cardiomyopathy 1D | 2023-04-11 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV003453150 | SCV004181303 | likely pathogenic | Cardiomyopathy, familial restrictive, 3 | 2023-04-11 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV001004907 | SCV004181304 | likely pathogenic | Hypertrophic cardiomyopathy 2 | 2023-04-11 | criteria provided, single submitter | clinical testing | |
Genomics England Pilot Project, |
RCV001004907 | SCV001760002 | likely pathogenic | Hypertrophic cardiomyopathy 2 | no assertion criteria provided | clinical testing |