ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.446G>A (p.Arg149His) (rs397516466)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare 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(in cis; M orales 2010), as well as in 2 infants with DCM who inherited this variant from a n unaffected parent (LMM unpublished).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 2018-08-27 criteria provided, single submitter clinical testing The R139H pathogenic variant in the TNNT2 gene has previously been reported in association with DCM (Morales et al., 2010; Walsh et al., 2017). Morales et al. (2010) identified this variant in an individual with late-onset DCM requiring cardiac transplant who also harbored an intronic variant in the TNNT2 gene on the same allele (in cis). This variant has also been identified in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and was found to segregate with disease in affected relatives from at least two unrelated families. In addition, a different likely pathogenic variant affecting the same residue (R139C) has been reported in association with DCM (Chami et al., 2014; Pugh et al., 2014; Walsh et al., 2017). The R139H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect and functional studies demonstrated that the R139H variant results in decreased calcium sensitivity, affecting protein function (Morales et al, 2010). Furthermore, other pathogenic or likely pathogenic variants in nearby residues (R134G, R141W, R141Q) have been reported in HGMD in association with DCM (Stenson et al., 2014), further supporting the functional importance of this region of the protein.
Invitae RCV000527920 SCV000646900 pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2020-06-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 139 of the TNNT2 protein (p.Arg139His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals with dilated cardiomyopathy and observed to segregate with dilated cardiomyopathy in several families (PMID: 20973921, 27532257, Invitae). This variant has been reported to affect TNNT2 protein function (PMID: 20973921). For these reasons, this variant has been classified as Pathogenic.
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.

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