ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.446G>A (p.Arg149His)

dbSNP: rs397516466
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000036590 SCV000060245 uncertain significance not specified 2014-07-31 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Arg139His v ariant in TNNT2 has been identified by our laboratory in 1 adult with DCM, who a lso carried the 690-6G>A varint in TNNT2 on the same copy of the gene (in cis; M orales 2010), as well as in 2 infants with DCM who inherited this variant from a n unaffected parent (LMM unpublished). One of these infants carried a second var iant in TNNT2 on the other copy of the gene (in trans) that may also be contribu ting to disease. In addition, this variant was absent from large population stud ies. Arginine (Arg) at position 139 is highly conserved in evolution and the cha nge to histidine (His) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is es timated to be correct 94% of the time (Jordan 2011). In addition, another varian t at the same position (Arg139Cys) as been identified in 1 family with DCM sugge sting that changes to this residue are not tolerated. Studies have shown that th is variant affects the protein?s function, though it is unclear if this effect w ould result in disease (Morales 2010). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the Arg139His variant is un certain.
GeneDx RCV000159295 SCV000209241 pathogenic not provided 2022-02-04 criteria provided, single submitter clinical testing Identified in patients with DCM in published literature (Morales et al., 2010; Walsh et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a decrease in calcium sensitivity, damaging protein function (Morales et al, 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 20973921, 29367539, 28352236, 21310275, 31521807, 33019804, 32880476, 33500567, 33906374)
Invitae RCV000527920 SCV000646900 pathogenic Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3 2021-08-24 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000159295 SCV000927760 likely pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000036590 SCV001362088 uncertain significance not specified 2019-04-08 criteria provided, single submitter clinical testing Variant summary: TNNT2 c.416G>A (p.Arg139His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 244976 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.416G>A has been reported in the literature in individuals affected with Cardiomyopathy (Morales_2010, Pugh_2014, Walsh_2017). The initial publication by Morales et al (2010), reported the presence of this variant in cis with another intronic TNNT2 variant (c.690-6G>A) that the authors considered to be of unknown significance. However the estimated penetrance of Cardiomyopathy (0.33) due to this variant appears to be lower than expected (0.4), as the variant was also identified in the unaffected offspring of the proband with the same TNNT2 genotype (Morales_2010). Therefore, no conclusions can be drawn from these data. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity in measures of maximal force of recovery in addition to desensitization of myofilaments to calcium at pH 6.5. However, the authors conclude that a 20% reduction in maximal force recovery represents a significant finding sufficient to explain the pathophysiology of late onset DCM brought on by fatty inflitration of the right ventricle (Morales_2010). Additional independent confirmation of these functional findings is awaited. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.