ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.548G>A (p.Arg183Gln) (rs397516471)

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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 RCV000036597 SCV000060252 likely pathogenic Primary dilated cardiomyopathy 2018-10-10 criteria provided, single submitter clinical testing The p.Arg173Gln variant in TNNT2 has been identified 3 individuals with DCM (1 w ith infantile onset and 1 with prenatal onset ) and segregated with disease in 6 affected relatives with varying ages of onset from 2 families (Van Acker 2009, Ferlund 2017, LMM data). It was absent from large population studies. Computatio nal prediction tools and conservation analysis are consistent with pathogenicity . Two additional variants involving this codon (p.Arg173Gly and p.Arg173Trp) hav e been identified in individuals with DCM, and p.Arg173Trp is classified as path ogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP criteria ap plied: PM2, PM5, PP1_Moderate, PP3, PS4_Supporting.
GeneDx RCV000159340 SCV000209286 pathogenic not provided 2019-01-15 criteria provided, single submitter clinical testing The R173Q pathogenic variant in the TNNT2 gene has been reported previously in multiple unrelated individuals with DCM and was found to segregate with disease in multiple affected individuals from at least three families (Van Acker et al., 2010; Lakdawala et al., 2012; Haas et al., 2015; Chauveau et al., 2017; Fernlund et al., 2017). The R173Q variant was initially reported in an infant with prenatal-onset DCM and segregated with DCM in four relatives from this family (Van Acker et al., 2010). Additionally, R173Q has been observed in two other individuals referred for DCM genetic testing at GeneDx, and parental testing showed this variant occurred de novo in one individual, although identity studies were not performed. The R173Q variant is not observed in large population cohorts (Lek et al., 2016). R173Q results in a semi-conservative amino acid substitution and in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, a pathogenic missense variant at the same residue (R173W) has been reported in the Human Gene Mutation Database in association with DCM (Stenson et al., 2014), further supporting the functional importance of this residue.
Invitae RCV000233887 SCV000285653 pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-09-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 173 of the TNNT2 protein (p.Arg173Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with dilated cardiomyopathy (DCM) in one family and has also observed in other unrelated individuals with DCM (PMID: 19324435, 22464770, 28669108). ClinVar contains an entry for this variant (Variation ID: 43649). A computational algorithm designed to assess the pathogenicity of variants in TNNT2 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). Furthermore, a different missense substitution at this codon (p.Arg173Trp) is reported to be deleterious (PMID: 24205113, 24367593). This indicates that the p.Arg173 residue is important for TNNT2 protein function. Variants that disrupt the p.Arg173 amino acid residue in TNNT2 have been observed in affected individuals (PMID: 24119082). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000159340 SCV000747940 likely pathogenic not provided 2017-06-05 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000159340 SCV000280528 likely pathogenic not provided 2011-12-29 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.Arg173Gln has been previously associated with DCM—and shown to segregate with disease in five affected members of the same family, including one sudden cardiac death. It has also been reported in another, unrelated case of sudden cardiac death. Van Acker et al. (2009) reported this variant to co-segregate with disease in five individuals from three generations of a family affected by DCM. The family’s race is not mentioned, but the researchers were located in Belgium. The proband had prenatal-onset disease (identified by fetal echocardiogram), and her brother also had DCM as a newborn; they and three other clinically affected relatives carried the Arg173Gln variant. This includes the proband’s mother and maternal uncle (the uncle’s affected son was not tested for the variant). It also includes the maternal grandmother, who had died suddenly of “arrhythmia” at the age of 47 and could not be tested, but her husband tested negative for the variant. The proband’s sister, the only unaffected mutation carrier, remained asymptomatic and had normal findings on echocardiography at the age of 21 years. In addition, Hernandez Del Rincon et al. (2011) reported in a poster session that they found this variant in a case of sudden cardiac death in Spain (19th International Association of Forensic Sciences World Meeting). The brief poster abstract does not contain additional phenotype data for the deceased, such as whether DCM was detected, although it mentions that a complete autopsy was performed. Variation at this and nearby loci of TNNT2 has been associated with disease. Arg173Trp (another variant at this same codon) has been seen in at least 3 unrelated individuals with cardiomyopathy and shown to segregate with disease in 4 members of a SCICD family with DCM (please see that variant analysis). Ala172Ser has been reported as a pathogenic mutation causing DCM; Glu163Lys, Glu163Arg, and Ser179Phe have been reported as pathogenic mutations causing HCM (Willott et al. 2010; Harvard Sarcomere Protein Gene Mutation Database). This is a chemically semi-conservative amino acid change: The variant substitutes a positively-charged amino acid (Arginine) with a polar, uncharged amino acid (Glutamine). The Arginine at position 173 is highly conserved across vertebrate evolution, although in zebrafish and medaka fish it is instead a positively-charged Lysine and in lamprey a Methionine. In silico analysis (PolyPhen-2) predicts the Arg173Gln variant to be “probably damaging.” Van Acker et al. (2009) did not observe the variant in 100 presumably healthy control individuals. Their race is not mentioned, but the study was conducted in Belgium. The variant was not seen in 3509 Caucasian individuals in NHLBI’s Exome Variant Server, nor in 1869 African American individuals ( The phenotype of these individuals is not publicly available, however the cohort has been screened to exclude those with evidence of Mendelian cardiac disease. The variant is not reported in 1000 Genomes ( (as of December 29, 2011). This contains 70 individuals of Colombian ancestry as well as over 400 Europeans. The patient’s father’s side of the family is Colombian and her mother’s side of the family includes Northern European Caucasian as well as Native American ancestry. The extensive Caucasian control data is most applicable, therefore, if her mother’s side of the family is the one affected. Assessment: Given the strong segregation data for this variant (albeit in only one family), the likely relevance of the Caucasian control data to that family, and two independent reports of sudden cardiac death associated with the variant, we believe Arg173Gln in TNNT2 is likely to be disease causing. In addition, another variant at this same amino acid residue (Arg173Trp) has segregated with disease in 3 members of a SCICD family with DCM, bolstering the functional importance of this site in the protein. It is therefore appropriate to use for predictive genetic testing for family members. Once the patient’s parents and other family members have been phenotyped, we may be in a position to strengthen this conclusion with segregation data. It is worth considering that the severity and early onset of the patient’s disease could be suggestive of two variants, possibly one from each side of the family.

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