ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.421C>T (p.Arg141Trp) (rs74315380)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000030567 SCV000060239 likely pathogenic Primary dilated cardiomyopathy 2013-09-30 criteria provided, single submitter clinical testing The Arg131Trp variant in TNNT2 has been identified in 1 individual with LVNC whe re it was reported to have occurred de novo (Klaassen 2008) and has now been ide ntified by our laboratory in 2 individuals with DCM. It was not identified in la rge population studies. Additionally, studies have shown that the Arg131Trp vari ant alters calcium binding properties of the thin filaments (Robinson 2007, Lui 2012). However, these in vitro assays may not accurately represent biological fu nction. Arginine (Arg) at position 131 is highly conserved in mammals and across evolutionarily distant species and the change to tryptophan (Trp) was predicted to be pathogenic using a computational tool clinically validated by our laborat ory. This tool's pathogenic prediction is estimated to be correct 94% of the tim e (Jordan 2011). In summary, this variant is likely to be pathogenic, though add itional studies are required to fully establish its clinical significance.
GeneDx RCV000159291 SCV000209237 pathogenic not provided 2018-01-29 criteria provided, single submitter clinical testing p.Arg131Trp (CGG>TGG): c.391 C>T in exon 10 of the TNNT2 gene (NM_001001430.1). The Arg131Trp mutation in the TNNT2 gene has been reported in association with cardiomyopathy (Mogensen J et al., 2004; Klassen S et al., 2008; Lakdawala N et al., 2012). Mogensen et al. initially identified the Arg131Trp mutation in an individual with DCM who had two other affected relatives (one had a sudden death at age 16 and the other died of heart failure at 34 years of age). Functional studies of the mutated protein showed an altered troponin protein-protein interaction (Mogensen J et al., 2004). The Arg131Trp mutation was also identified in a patient with DCM and it was also reported as de novo in another patient with left ventricular non-compaction (LVNC) (Lakdawala N et al., 2012; Klassen S et al., 2008). Collectively, these studies did not observed Arg131Trp in more than 700 control alleles and it was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Arg131Trp in the TNNT2 gene is interpreted as a disease-causing mutation. Hereditary dilated cardiomyopathy (DCM) is primarily an autosomal dominant disease characterized by left ventricular enlargement and systolic dysfunction in the absence of other cardiac, systemic or environmental causes (Hershberger R et al., 2009). Left ventricular noncompaction (LVNC) is a rare cardiomyopathy characterized by deep trabeculations with intertrabecular recesses in the ventricular wall (Callis T et al., 2010). LVNC and DCM can lead to progressive deterioration of cardiac function, arrhythmias, and sudden cardiac death, although some individuals may be asymptomatic. Hereditary DCM is most frequently caused by mutations in genes encoding for sarcomeric proteins in the cardiac muscle, or in the gene encoding the nuclear envelope protein lamin A/C (LMNA). Less commonly, DCM and LVNC can be caused by mutations in genes associated with metabolic or mitochondrial disorders (Callis T et al., 2010; Hershberger R et al., 2009). Mutations in the TNNT2 gene have been reported in 5-15% of patients with autosomal dominant familial hypertrophic cardiomyopathy, often characterized by minimal left ventricular hypertrophy (LVH) but a high incidence of sudden cardiac death (Moolman J et al., 1997; Cirino A et al., 2011). Mutations in TNNT2 have been reported less frequently in association with autosomal dominant familial dilated cardiomyopathy (Hershberger R et al., 2009). The variant is found in DCM panel(s).
Invitae RCV000524541 SCV000541919 pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-08-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 131 of the TNNT2 protein (p.Arg131Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs74315380, ExAC 0.002%). This variant has been reported in the literature co-segregating with disease in one family affected with dilated cardiomyopathy (DCM) and left ventricular non compaction (LVNC) (PMID: 15542288). It has been shown to arise de novo in one individual affected with LVNC (PMID: 18506004). It has also been reported in unrelated individuals affected with DCM and LVNC (PMID: 21551322, 24119082). ClinVar contains an entry for this variant (Variation ID: 12415). Experimental studies have shown that this variant disrupts normal troponin function in in vitro motility assays (PMID: 15542288, 17932326, 22675533, 15923195). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000588329 SCV000697562 likely pathogenic Cardiovascular phenotype 2017-06-22 criteria provided, single submitter clinical testing Variant summary: The TNNT2 c.391C>T (p.Arg131Trp) variant results in a non-conservative amino acid substitution located in the tropomyosin binding domain of the protein (Mogensen_2004, Klaassen_2008). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/116588 control chromosomes at a frequency of 0.0000086, which does not exceed the estimated maximal expected allele frequency of a pathogenic TNNT2 variant (0.000175). This variant has been found in 4 probands (1st with DCM, 2nd with LVNC, 3rd with DCM/LVNC, and 4th with DCM) in the reported literature. In the first family, it was found to co-segregate with DCM in at least two affected members. In second family, the variant was found to be de novo in the affected proband; however, it is not specified whether paternity was confirmed. In the third family, affected mother was available for genotyping but she did not carry the variant. From the results of third family, authors assume the variant either to be VUS or disease-causing having reduced penetrance. The unaffected father in the family was not available for genotyping. Though this lack of co-segregation may indicate that it may not be pathogenic, the possibility that another familial variant was explaining the phenotype in the mother which remained untransmitted in the proband cannot be ruled out. In addition, this variant could have a reduced penetrance and could have been transmitted from the unaffected father, or it could have originated de novo. The variant has also been reported in two patients with DCM by LMM/PH (unpublished findings). Several independent functional studies dating from 2004 to 2016 have demonstrated that this variant results in a depressed myofilament calcium sensitivity in alpha-MHC (myosin heavy chains) thereby inducing a more severe DCM-like contractile phenotype against an alpha-MHC background. These results are consistent with an established molecular mechanism of disease due to an alteration in the contractile dynamics in the presence of mutations in TNNT2. Three diagnostic centers via ClinVar interpret the variant as pathogenic/likely pathogenic, without evidence for independent evaluation. There are also other potentially pathogenic missense variants around this variant (such as such as p.E128K, p.R130C and p.R134G), suggesting a notion that the region may have a functional importance. Taken all evidences together, this variant is classified as Likely Pathogenic until additional reports demonstrating unequivocal co-segregation with disease in independent families with multiple affected and unaffected members are obtained.
Ambry Genetics RCV000588329 SCV000736576 likely pathogenic Cardiovascular phenotype 2016-04-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s)
OMIM RCV000013226 SCV000033473 pathogenic Left ventricular noncompaction 6 2008-06-03 no assertion criteria provided literature only

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