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

dbSNP: rs397516466

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017309	SCV000060245	likely pathogenic	Primary dilated cardiomyopathy	2023-02-07	criteria provided, single submitter	clinical testing	The p.Arg139His variant in TNNT2 has been reported in at least 8 individuals with dilated cardiomyopathy (DCM), including 2 infants, and segregated with disease in at least 8 affected relatives from 2 families. However, this variant has also been found in unaffected relatives (in some individuals in their 50s) and in unaffected parents of infants with DCM (Morales 2010 PMID: 20973921, Millat 2014 PMID: 24721642, Li 2020 PMID: 31521807, Hey 2020 PMID: 33019804, Verdonschot 2020 PMID: 32880476, Ware 2021 PMID: 33906374, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 43642) and has been identified in 0.00088% (1/113310) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). In vitro functional studies provide some evidence that this variant impacts protein function (Morales 2010 PMID: 20973921), and computational prediction tools and conservation analyses suggest that this variant may impact the protein. Another variant involving this codon (p.Arg139Cys) has been identified in individuals with DCM. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PS4_Moderate, PP1_Moderate, PM2_Supporting, PP3, PS3_Supporting.
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	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 139 of the TNNT2 protein (p.Arg139His). This variant is present in population databases (rs397516466, gnomAD 0.0009%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 20973921, 27532257; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43642). 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. Experimental studies have shown that this missense change affects TNNT2 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.