Submissions for variant NM_001276345.2(TNNT2):c.712C>G (p.Gln238Glu)

dbSNP: rs730881108

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159310	SCV000209256	uncertain significance	not provided	2013-03-18	criteria provided, single submitter	clinical testing	p.Gln228Glu (CAG>GAG): c.682 C>G in exon 13 of the TNNT2 gene (NM_001001430.1). The Gln228Glu variant in the TNNT2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gln228Glu results in a semi-conservative amino acid substitution of a neutral, polar Glutamine with a negatively charged Glutamic acid at a position that is conserved mammalian species. The Gln228Glu variant 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. However, in silico analysis predicts Gln228Glu is benign to the protein structure/function. Also, no mutations in nearby codons have been reported in association with cardiomyopathy. With the clinical and molecular information available at this time, we cannot definitively determine if Gln228Glu is a disease-causing mutation or a rare benign variant. 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, 2003). 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). The variant is found in HCM panel(s).
Invitae	RCV001850239	SCV002273080	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2022-02-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 228 of the TNNT2 protein (p.Gln228Glu). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 181627). This variant has not been reported in the literature in individuals affected with TNNT2-related conditions. This variant is not present in population databases (gnomAD no frequency).
Genome-Nilou Lab	RCV003453237	SCV004181247	uncertain significance	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453238	SCV004181248	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453236	SCV004181249	uncertain significance	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998391	SCV004837637	uncertain significance	Cardiomyopathy	2023-11-30	criteria provided, single submitter	clinical testing