ClinVar Miner

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

dbSNP: 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,Mass General Brigham 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 Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3 2021-10-05 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 missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) (PMID: 22517884, 24205113). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects TNNT2 function (PMID: 22517884, 24367593). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000223699 SCV000616898 pathogenic not provided 2022-01-05 criteria provided, single submitter clinical testing Published functional studies in cardiomyocytes exhibited altered Ca2+ handling and impaired myofilament regulation (Sun et al., 2012); Not observed in large population cohorts (gnomAD); 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: 32458740, 30624779, 26095046, 26237594, 28315121, 27296521, 24119082, 20800588, 28246128, 24367593, 24205113, 22517884, 27335446, 27237981, 24576884, 25690476, 28573431, 27721795, 25548614, 26265630, 23074333, 30871747, 30565988, 31373515, 31514951, 31931689, 33083013, 33025817, 33087929)
Centogene AG - the Rare Disease Company RCV001250182 SCV001424507 pathogenic Dilated cardiomyopathy 1D 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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