ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.506G>A (p.Arg169Gln) (rs45501500)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036595 SCV000060250 uncertain significance not specified 2016-05-27 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg159Gln variant in TNNT2 has been identified in 1 Caucasian individual with peripartum DCM, 1 Caucasian individual with LVNC, and 1 Black individual with DCM. It segre gated with disease in 1 affected relative (Hershberger 2008, Morales 2010, LMM u npublished data). Studies have shown that the p.Arg159Gln variant may affect pro per myocyte function (Hershberger 2009); however, this in vitro assay may not ac curately represent biological function. This variant has not been identified by large population studies and was predicted to be pathogenic using a computationa l 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 the re is some suspicion for a pathogenic role, the clinical significance of the p.A rg159Gln variant is uncertain.
GeneDx RCV000225721 SCV000209247 likely pathogenic not provided 2011-11-01 criteria provided, single submitter clinical testing p.Arg159Gln (R159Q) CGA>CAA: c.476 G>A in exon 11 of the TNNT2 gene (NM_001001430.1). The R159Q variant has been reported previously in a single individual with idiopathic dilated cardiomyopathy whose heart failure onset was associated with pregnancy (Hershberger R et al., 2008; Hershberger R et al., 2009). R159Q was reported to decrease calcium sensitivity of the myofilaments, which could lead to altered contractility dynamics of the heart (Hershberger R et al., 2009). R159Q is a semi-conservative amino acid substitution as these residues share similar properties, but differ in size, charge, or other properties which may impact secondary structure. The R159 residue is only conserved through mammals but is class conserved throughout evolution, with in silico analysis suggesting this variant to be benign to the protein structure/function. Mutations in nearby residues (R151C, A157S, E163K) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Furthermore, the R159Q variant was not observed in approximately 6500 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 variant is found in DCM,CARDIOMYOPATHY panel(s).
Invitae RCV000703215 SCV000832104 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2020-04-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 159 of the TNNT2 protein (p.Arg159Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with peripartum dilated cardiomyopathy (PMID: 20031601). ClinVar contains an entry for this variant (Variation ID: 43647). Experimental studies have shown that this missense change is associated with decreased calcium sensitivity of force development in cardiac myocytes (PMID: 20031601). 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000036595 SCV000280525 uncertain significance not specified 2012-03-14 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg159Gln (c.476G>A) in TNNT2 gene. This variant has been reported in two unrelated cases of DCM . One proband was a Caucasian female who was diagnosed with DCM at 20 years of age, 1 week postpartum (Hershberger et al 2008, Hershberger et al 2009, Morales et al 2010). The other was a case of infantile DCM diagnosed at 4 months of age with transplant at 12 years of age (Hershberger et al 2009, Rampersaud et al 2010). There is no co-segregation data on the variant. This is a semi-conservative amino acid substitution with a positively charged Arginine replaced with a neutral Glutamine. Conservation analysis indicates that Arginine is conserved at this position only through mammals but is class conserved throughout evolution. In silico analysis yields conflicting results with SIFT predicting the amino acid change to be tolerated while PolyPhen predicts the substitution to the probably damaging to final protein. Missense variants in nearby codons (p.Arg151Cys, p.Ala157Ser and p.Glu163Lys) have been reported in association with cardiomyopathy. Hershberger et al (2009) reported that p.Arg159Gln affects Ca2+ sensitivity of the myofilaments; this is an integral part of force/contraction generation in the cardiomyocyte. The above authors report the absence of the variant in 253 presumably healthy control individuals. From this control group 188 were Caucasian, 24 African American, 22 Asian and 19 were of Hispanic ancestry. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~5,000 Caucasian and African American individuals (as of December 2011). The variant is also listed in dbSNP (rs45501500), which notes that 246 individuals of varying ethnicity drawn from population DNA samples from Coriell were all wildtype.

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