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

dbSNP: rs397516471

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2021-12-08	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 43649; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22464770, 25163546, 19324435, 28588840, 28669108, 29367539, 33019804)
Invitae	RCV000233887	SCV000285653	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 173 of the TNNT2 protein (p.Arg173Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 19324435, 22464770, 28669108). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43649). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg173 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24119082). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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
Ambry Genetics	RCV002336123	SCV002644166	pathogenic	Cardiovascular phenotype	2018-09-19	criteria provided, single submitter	clinical testing	The p.R173Q pathogenic mutation (also known as c.518G>A), located in coding exon 10 of the TNNT2 gene, results from a G to A substitution at nucleotide position 518. The arginine at codon 173 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in multiple probands with dilated cardiomyopathy (DCM) and has been shown to segregate with disease (Van Acker H et al. Int. J. Cardiol., 2010 Oct;144:307-9; Lakdawala NK et al. J. Card. Fail., 2012 Apr;18:296-303; Chauveau S et al. Clin Case Rep, 2017 Jun;5:923-926; Fernlund E et al. Pediatr Cardiol, 2017 Aug;38:1262-1268). In addition, another alteration affecting the same amino acid, p.R173W (c.517C>T), has been reported in association with DCM (Sun N et al. Sci Transl Med, 2012 Apr;4:130ra47). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab	RCV001594378	SCV004181315	likely pathogenic	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450709	SCV004181316	likely pathogenic	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450708	SCV004181317	likely pathogenic	Hypertrophic cardiomyopathy 2	2023-04-11	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 (http://evs.gs.washington.edu/EVS/). 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 (http://browser.1000genomes.org/index.html) (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.
KTest Genetics, KTest	RCV001594378	SCV001499978	pathogenic	Dilated cardiomyopathy 1D		no assertion criteria provided	clinical testing