Submissions for variant NM_001276345.2(TNNT2):c.274G>A (p.Gly92Arg)

dbSNP: rs727504255

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154228	SCV000203883	likely pathogenic	Hypertrophic cardiomyopathy	2016-03-30	criteria provided, single submitter	clinical testing	The p.Gly82Arg variant in TNNT2 has been reported in 2 individuals with HCM, seg regated with disease in 4 individuals (including 2 obligate carriers)(Maron 2008 , Judge 2009), and was absent from large population studies. This 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). In summary, although additional studies are required to fully establish its clinical significance, the p.Gly82Arg variant is likely path ogenic.
GeneDx	RCV000159274	SCV000209220	pathogenic	not provided	2013-05-29	criteria provided, single submitter	clinical testing	p.Gly82Arg (GGA>AGA): c.244 G>A in exon 8 of the TNNT2 gene (NM_001001430.1). The Gly82Arg mutation in the TNNT2 gene has been reported in one patient with HCM and left ventricular apical aneurysm (Maron M et al., 2008). Gly82Arg results in a non-conservative amino acid substitution of a non-polar Glycine with a positively charged Arginine at a position that is conserved across species. In silico analysis predicts Gly82Arg is probably damaging to the protein structure and function. Mutations in nearby residues (Ile79Asn, Pro80Ser, Glu83Lys, Glu83Asp, Val85Leu) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the Gly82Arg mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Hereditary hypertrophic cardiomyopathy (HCM) is primarily an autosomal dominant disease characterized by myocardial hypertrophy in the absence of other cardiac or systemic causes. HCM is most frequently caused by mutations in genes coding for sarcomeric proteins in the cardiac muscle leading to myocyte disarray, a hallmark feature of HCM. Less commonly, ventricular hypertrophy is a presenting feature of genetic systemic disorders, such as Danon disease, Fabry disease, or mitochondrial cardiomyopathy. HCM has a variable clinical presentation; including palpitations, chest pain, heart failure, syncope, or sudden death, although some individuals may be asymptomatic (Marian A et al., 1995; Maron B, 2002). Mutations in the TNNT2 gene have been reported in 5-15% of patients with autosomal dominant familial hypertrophic cardiomyopathy, often characterized by minimal left ventricular hypertrophy (LVH) but a high incidence of sudden cardiac death (Moolman J et al., 1997; Cirino A et al., 2011). Mutations in TNNT2 have been reported less frequently in association with autosomal dominant familial dilated cardiomyopathy (Hershberger R et al., 2009). In summary, Gly82Arg in the TNNT2 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).
Genome-Nilou Lab	RCV003453154	SCV004181522	likely pathogenic	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453155	SCV004181523	likely pathogenic	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453153	SCV004181524	likely pathogenic	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing