ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.281G>C (p.Arg94Thr) (rs397516452)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036568 SCV000060223 uncertain significance not specified 2014-12-30 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg84Thr variant in TNNT2 has been identified by our laboratory in 2 Asian adults with HC M and segregated with disease in one affected family member. It was absent from large population studies, including a cohort of Asian individuals (http://exac.b roadinstitute.org). Arginine (Arg) at position 84 is conserved in mammals, but n ot in evolutionary distant species. However, the change to threonine (Thr) was p redicted 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, while there is suspicion for a pathogenic r ole, the clinical significance of the p.Arg84Thr variant is uncertain.
GeneDx RCV000159277 SCV000209223 likely pathogenic not provided 2018-03-22 criteria provided, single submitter clinical testing p.Arg84Thr (AGA>ACA): c.251 G>C in exon 8 of the TNNT2 gene (NM_001001430.1) that is likely pathogenic was identified in the TNNT2 gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R84T 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. The R84T variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (F87C, D86A, V85L, E83D, E83K) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. 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).
Ambry Genetics RCV000244818 SCV000319791 uncertain significance Cardiovascular phenotype 2015-06-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence

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