ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.634C>T (p.Arg212Trp) (rs45586240)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620262 SCV000737236 uncertain significance Cardiovascular phenotype 2017-02-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Blueprint Genetics RCV000157539 SCV000207285 likely pathogenic Primary dilated cardiomyopathy 2014-04-29 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768716 SCV000900086 likely pathogenic Cardiomyopathy 2016-08-16 criteria provided, single submitter clinical testing
GeneDx RCV000159308 SCV000209254 pathogenic not provided 2017-12-15 criteria provided, single submitter clinical testing The R205W pathogenic variant in the TNNT2 gene has been reported in association with DCM (Hershberger et al., 2008; Hershberger et al., 2009; Rampersaud et al., 2011; Walsh et al., 2017). The R205W variant was identified in a 6 month old patient who was diagnosed with post-viral DCM and underwent heart transplantation at 12 years old (Hershberger et al., 2009; Rampersaud et al., 2011). Additionally, R205W was noted to segregate with disease in this family, although additional details were not provided (Rampersaud et al., 2011). R205W has also been identified both independently of and in conjunction with additional cardiogenetic variants in two other individuals referred for cardiomyopathy genetic testing at GeneDx; however, thus far, segregation data is limited or absent due to the lack of clinical information provided and/or insufficient participation by informative family members. The R205W variant is not observed in large population cohorts (Lek et al., 2016). The R205W 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. Furthermore, functional studies indicate R205W leads to decreased calcium sensitivity of force development in cardiac myocyte fibers (Hershberger et al., 2009). Other missense variants in the same residue (R205L and R205Q) have been reported in Human Gene Mutation Database in association with DCM (Stenson et al., 2014), further supporting the functional importance of this residue.
Invitae RCV000823611 SCV000964476 likely pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 205 of the TNNT2 protein (p.Arg205Trp). 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 observed in several individuals affected with dilated cardiomyopathy or hypertrophic cardiomyopathy (PMID: 20031601, 23349452, 27532257). ClinVar contains an entry for this variant (Variation ID: 180554). Experimental studies have shown that this missense change decreases calcium sensitivity (PMID: 20031601). This variant disrupts the p.Arg205 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15542288, 26498512), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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