ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.547C>T (p.Arg183Trp) (rs727503512)

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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 RCV000223622 SCV000271467 pathogenic Primary dilated cardiomyopathy 2016-01-07 criteria provided, single submitter clinical testing The p.Arg173Trp variant in TNNT2 has been reported in 3 families with DCM, segre gated with disease in >15 affected relatives (Sun 2012, Merlot 2012, Campbell 20 13), and was absent from large population studies. In vitro functional studies a lso provide some evidence that this variant may impact protein function (Sun 201 2, Sommese 2013). In summary, this variant meets our criteria to be classified a s pathogenic for DCM in an autosomal dominant manner based on segregation studie s, absence from controls, and functional data.
Invitae RCV000474826 SCV000541932 pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2020-10-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 173 of the TNNT2 protein (p.Arg173Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature co-segregating with disease in families affected with dilated cardiomyopathy (DCM) (PMID: 22517884, 24205113). Experimental studies have shown that this variant causes a higher susceptibility to mechanical stress in IPS cell-derived cardiomyocytes, decreases calcium sensitivity, and compromises contractility in the sarcomere (PMID: 22517884, 24367593). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000223699 SCV000616898 pathogenic not provided 2018-12-12 criteria provided, single submitter clinical testing The R173W variant in the TNNT2 gene has been reported to segregate with DCM in a large five-generation pedigree, with 12 affected family members all harboring R173W (Campbell et al., 2013). Campbell et al. (2013) also reported R173W segregated with DCM in a second family in the study registry. The R173W variant is not observed in large population cohorts (Lek et al., 2016). The R173W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect, consistent with functional studies in cardiomyocytes generated from induced pluripotent stem cells from patients of a family harboring R173W, which exhibited altered Ca2+ handling and impaired myofilament regulation (Sun et al., 2012). Another variant in the same residue (R173Q) has been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014), further supporting the functional importance of this residue and this region of the protein. We interpret R173W as a pathogenic variant
Centogene AG - the Rare Disease Company RCV001250182 SCV001424507 pathogenic Left ventricular noncompaction 6 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223699 SCV000280527 likely pathogenic not provided 2011-08-25 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.Arg173Trp (c. 517C>T). At the time of testing this variant was novel (had not been reported in association with cardiomyopathy or as a benign common variant), however it has now been seen in a total of 3 unrelated individuals with cardiomyopathy. An unpublished study conducted in our laboratory demonstrated segregation of the variant in a total of four family members with a DCM diagnosis (Liu et al. 2012 published iPSC studies using this family's DNA). Since testing was completed 3 years ago we contacted the testing lab for an update on this variant and they shared that 1 additional individual (no relation to our proband) tested for DCM was genotype positive for the variant. In addition, Millat et al 2010 reported this variant in a patient with HCM (few clinical details and no segregation data were provided). This is a non conservative amino acid change with a hydrophilic, polar Arginine replaced with a hydrophobic, nonpolar Tryptophan. This variant has not been reported as a benign polymorphism (dbSNP, Google). A variant at the same codon, Arg173Gln, has been seen in at least 3 unrelated families with DCM and/or sudden death (including a SCICD family; please see that variant analysis) and shown to segregate with disease in 5 members of one published family with DCM. Variants in nearby codons (p.Ala172Ser and p.Ser179Phe) have been reported in association with cardiomyopathy (Stefanelli et al 2004 and Ho et al 2000). In silico analysis (PolyPhen) predicts the amino acid change to be damaging to protein structure/function. Arginine is highly conserved at residue 173 across species. This variant was not observed in 335 presumably healthy individuals of mixed ethnicity tested at the testing lab The variant is not listed in dbSNP or 1000 genomes.

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