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

dbSNP: rs727503512

Total submissions: 9

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	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 173 of the TNNT2 protein (p.Arg173Trp). This variant is not present in population databases (gnomAD 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. ClinVar contains an entry for this variant (Variation ID: 228409). 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. 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
Ambry Genetics	RCV002338676	SCV002644137	pathogenic	Cardiovascular phenotype	2020-03-25	criteria provided, single submitter	clinical testing	The p.R173W pathogenic mutation (also known as c.517C>T), located in coding exon 10 of the TNNT2 gene, results from a C to T substitution at nucleotide position 517. The arginine at codon 173 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been detected in several individuals with dilated cardiomyopathy (DCM) and has demonstrated strong segregation with DCM in multiple affected families (Sun N et al. Sci Transl Med, 2012 Apr;4:130ra47; Campbell N et al. PLoS ONE, 2013 Oct;8:e78104; Sousa A et al. Rev Port Cardiol, 2019 02;38:129-139). Studies using induced pluripotent stem cell cardiomyocytes from affected individuals have demonstrated functional impacts (Sun N et al. Sci Transl Med, 2012 Apr;4:130ra47; Sommese RF et al. PLoS ONE, 2013 Dec;8:e83403; Wu H et al. Cell Stem Cell, 2015 Jul;17:89-100; Dai Y et al. Sci Rep, 2020 Jan;10:209). Furthermore, an alternate amino acid substitution at this position, p.R173Q, has also been reported in multiple probands with 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab	RCV001250182	SCV004181319	pathogenic	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003454597	SCV004181320	pathogenic	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003454596	SCV004181321	pathogenic	Hypertrophic cardiomyopathy 2	2023-04-11	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.