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

dbSNP: rs45501500

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	uncertain significance	not provided	2021-06-23	criteria provided, single submitter	clinical testing	Reported in association with cardiomyopathy (Hershberger et al., 2008; Rampersaud et al., 2011; Walsh et al., 2017; Mazzarotto et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported to decrease calcium sensitivity of the myofilaments, which could lead to altered contractility dynamics of the heart (Hershberger et al., 2009); however, it is not known whether these findings are biological or clinically relevant in vivo; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20458009, 19412328, 27532257, 21483645, 31983221, 26582918, 27535533, 20031601)
Invitae	RCV000703215	SCV000832104	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 159 of the TNNT2 protein (p.Arg159Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 20031601, 27532257, 31983221, 33500567, 35653365, 36166435; Invitae). This variant is also known as p.Arg169Gln. ClinVar contains an entry for this variant (Variation ID: 43647). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 20031601). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798104	SCV002042849	uncertain significance	Cardiomyopathy	2019-08-15	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000225721	SCV002503361	uncertain significance	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470731	SCV002768058	likely pathogenic	Dilated cardiomyopathy 1D	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Functional studies have suggested loss-of-function, gain-of-function and dominant-negative mechanisms based on calcium sensitivity, contractibility and mouse models (PMID: 18612386, 32098556, 33025817). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. p.(Arg92Gln) has been described in families which has both dilated cardiomyopathy (DCM) and hypertrophic cardimyopathy (PMID: 26507537). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated troponin domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported in at least three unrelated individuals with DCM (ClinVar, PMID: 20458009, 19412328, 20031601, 27532257, 31983221), and has been described as both likely pathogenic and as a VUS (ClinVar, LOVD). Additionally, it has been observed in another individual with DCM and classified using ACMG guidelines as pathogenic. However, this publication is yet to be peer reviewed (Lesurf R, et al. (2020)). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies using porcine cardiac fibres demonstrated that this variant results in reduced calcium sensitivity (PMID: 20031601). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV004018798	SCV004968979	uncertain significance	Cardiovascular phenotype	2021-04-21	criteria provided, single submitter	clinical testing	The c.476G>A (p.R159Q) alteration is located in exon 11 (coding exon 10) of the TNNT2 gene. This alteration results from a G to A substitution at nucleotide position 476, causing the arginine (R) at amino acid position 159 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
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.