ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.311G>A (p.Arg104His) (rs397516457)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036575 SCV000060230 pathogenic Hypertrophic cardiomyopathy 2017-06-19 criteria provided, single submitter clinical testing The p.Arg94His variant in TNNT2 has been reported in at least 6 individuals with HCM, including 3 de novo occurrences (Ho 2009, Millat 2010, Ripoll-Vera 2016, W alsh 2016, LMM data, ClinVar Variation ID 43628). The variant also segregated wi th disease in 2 affected members of 1 family (Ripoll-Vera 2016), and was absent from large population studies. Arginine (Arg) at position 94 is highly conserved in mammals and across evolutionarily distant species and the change to histidin e (His) was predicted to be pathogenic using a computational tool clinically val idated by our laboratory. This tool's pathogenic prediction is estimated to be c orrect 94% of the time (Jordan 2011). In addition, 2 other likely disease-causin g variants at this position (p.Arg94Cys and p.Arg94Leu) have been reported in mu ltiple individuals with HCM (Varnava 1999, Walsh 2016). In summary, the p.Arg94H is variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner.
GeneDx RCV000159283 SCV000209229 pathogenic not provided 2018-08-24 criteria provided, single submitter clinical testing The R94H pathogenic variant in the TNNT2 gene has been published in association with HCM (Ho et al., 2009, Millat et al., 2010; Ripoll-Vera et al., 2016; Walsh et al., 2017). Ripoll-Vera et al. (2016) observed the R94H pathogenic variant in 3 family members; the 15 year old proband, his father and paternal aunt, all of whom were diagnosed with HCM. This variant was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes et al., 2015; Exome Variant Server), indicating it is not a common benign variant. Although R94H is a conservative amino acid substitution, the R94 residue is highly conserved across species. In addition, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, other missense variants affecting the same codon (R94C, R94L) and nearby codons (R92L, R92Q, R92W, K97N) have been reported in the Human Genome Mutation Database in association with HCM (Stenson et al., 2014), further supporting the functional importance of this region of the protein.
Invitae RCV000230630 SCV000285649 pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 94 of the TNNT2 protein (p.Arg94His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of hypertrophic cardiomyopathy (PMID: 2003160, 20624503, Invitae). Variants affecting this codon have been reported to affect TNNT2 protein function (PMID:11606294). This variant disrupts the p.Arg94 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been observed in individuals with TNNT2-related conditions (PMID: 10525521, 11606294, 10978365), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000619351 SCV000739953 likely pathogenic Cardiovascular phenotype 2016-05-25 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,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species

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