Submissions for variant NM_001276345.2(TNNT2):c.601-1G>A

gnomAD frequency: 0.00001  dbSNP: rs483352835

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000223749	SCV000209251	uncertain significance	not provided	2023-05-03	criteria provided, single submitter	clinical testing	Identified in patients with HCM and DCM in published literature (Van Driest et al., 2004; Rani et al., 2014; Walsh et al., 2017; Mazzarotto et al., 2020); at least one patient harbored an additional pathogenic variant in a cardiomyopathy-related gene; Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 24992688, 27532257, 15358028, 31983221)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000159305	SCV000272529	uncertain significance	not specified	2015-11-11	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The c.571-1G>A variant in TNNT2 has been reported in 4 individuals with cardiomyopathy (1 child DCM; 1 child LVNC; 1 child HCM and VT; 1 adult DCM) (Van Driest 2004, Rani 2014 , LMM unpublished data). Of note, the child with HCM also carried a pathogenic v ariant in MYH7 (Van Driest 2004). It has been identified in 2/23916 Asian chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs483352835). This variant occurs in the invariant region (+/- 1,2) and h as been shown to lead to the deletion of a single amino acid (Glu) (Van Driest 2 004). A small number of similar TNNT2 variants (single amino acid deletions and splice variants) are established as pathogenic for cardiomyopathy (DCM, HCM). In summary, while there is some suspicion for a pathogenic role, the clinical sign ificance of the c.571-1G>A variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475521	SCV000541924	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 11 of the TNNT2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TNNT2 cause disease. This variant is present in population databases (rs483352835, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with clinical features of TNNT2-related conditions (PMID: 24992688, 27532257, 31983221, 37652022). This variant is also known as c.601-1G>A. ClinVar contains an entry for this variant (Variation ID: 132940). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001189180	SCV001356415	likely benign	Cardiomyopathy	2025-03-12	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000223749	SCV002501197	uncertain significance	not provided	2022-01-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000475521	SCV002814393	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2021-10-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000223749	SCV003827714	uncertain significance	not provided	2020-12-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162554	SCV003866040	uncertain significance	Cardiovascular phenotype	2021-10-12	criteria provided, single submitter	clinical testing	The c.571-1G>A intronic alteration consists of a G to A substitution 1 nucleotides before coding exon 11 in the TNNT2 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003225029	SCV003921918	uncertain significance	Dilated cardiomyopathy 1D	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Functional studies have suggested loss-of-function, gain-of-function and dominant-negative mechanisms based on calcium sensitivity, contractibility and mouse models (PMID: 18612386, 32098556, 33025817). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. p.(Arg92Gln) has been reported to cause both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), even within the same family (PMID: 26507537). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0219 - This variant is intronic in an alternative transcript. However, it is a canonical splice site in both the transcript predominantly reported in ClinVar and on the transcript with the highest expression in heart (GTEx). (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site, is present in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0705 - No comparable canonical splice site variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported multiple times as a VUS (ClinVar, LOVD, PMID: 27532257, PMID: 30847666) and as likely pathogenic (ClinVar; PMID:37821546). It has been reported in an individual with severe early onset hypertrophic cardiomyopathy (HCM), who also harboured the well-known pathogenic p.(Arg453Cys) variant in the MYH7 gene (PMID: 15358028). Although this variant is reported to result in an in-frame deletion of p.(Gln201del), data was not shown and methods were not specified (PMID: 15358028). Additionally, this variant was identified in individuals with DCM (VCGS, PMID: 24992688) and HCM (PMID: 15358028), and in a fetus with noncompaction cardiomyopathy (PMID: 33553264). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genome-Nilou Lab	RCV003225029	SCV004173767	uncertain significance	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003445513	SCV004173768	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003445512	SCV004173769	uncertain significance	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001189180	SCV004821977	uncertain significance	Cardiomyopathy	2024-06-17	criteria provided, single submitter	clinical testing	This variant (also known as IVS11-1G>A) causes a G to A nucleotide substitution at the -1 position of intron 11 of the TNNT2 gene. Splice prediction tools suggest that this variant may impact RNA splicing. A functional study using patient-derived tissue for RNA analysis reported that this variant causes an in-frame deletion of one amino acid, however data was not shown (PMID: 15358028), and clinical relevance of this observation is unclear. This variant has been reported in eight individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 27532257, 30847666, 33495597, 37821546); one of these individuals also carried a pathogenic variant in the MYH7 gene (PMID: 15358028). This variant has also been reported in three individuals affected with dilated cardiomyopathy (PMID: 24992688, 31983221), in one individual affected with noncompaction cardiomyopathy (PMID: 33553264), and in three individuals affected with sudden unexplained death (PMID: 37821546). This variant has been identified in 5/249022 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ingles Laboratory, Garvan Institute Of Medical Research	RCV004586555	SCV005062011	benign	Hypertrophic cardiomyopathy	2024-03-26	criteria provided, single submitter	curation	We identified TNNT2; NM_001001430.3: c.571-1G>A (rs483352835) in 2 probands. Proband 1 was a male of Oceanian ancestry SCD in his early 20s with no cause identified following a comprehensive post-mortem investigation. Proband 2 was a 0-3 year-old child of Oceanian ancestry with RCM who died from rapidly progressive heart failure; in addition to the TNNT2 splice variant, a pathogenic variant in TNNI3 classified pathogenic as per ACMG guidelines was also identified. A total of 26 probands with a cardiac phenotype were reported (from clinical & research labs, ClinVar, and in Literature). Of these, 24 had a known cardiac phenotype, including 15 with HCM (including two diagnosed on autopsy following SCD), five with DCM (two presented at less than three years of age), three with sudden unexplained death, and one individual with high-burden premature ventricular contractions, syncope, and a family history of SCD. One individual lacked a specific diagnosis but had a family history of SCD, and in another, the diagnosis was not available. Four probands reported a family history of SCD in a close relative. Evidence of co-segregation with disease in families was reported for one family with HCM, with the variant identified in two affected relatives. At least four probands (15%) had an additional pathogenic variant that explained their cardiac phenotype. Ancestry was available for 22 probands, of which 21 probands were reported as having Oceanian ancestry, including Aotearoa New Zealand Māori, Samoan, Tongan, Polynesian, Pacific Islander, Australian Aboriginal and Torres Strait Islander, and Hawaiian. Among publicly available databases, TNNT2:c.571-1G>A (rs483352835) was present in gnomAD v4.0.0 in 13/780,762 (0.002%) alleles, with the highest sub-population frequencies among South Asian (5/74,486; 0.007%) and East Asian (1/41,260; 0.002%) alleles. Within Genome Asia 100K Project, the variant was present in 6/148 (4.1%) chromosomes in the Oceanian population, with a frequency of 2/4 (50%) chromosomes in the 2 Australian participants (one homozygote), and 4/140 (2.9%) in Papuan alleles. Among ancestry-relevant population sequencing data unavailable in the public domain, the variant was absent in the Taiwanese Biobank (0/3032; 0%). Within the Pacific Islands Rheumatic Heart Disease Genetics Network, the variant was present at a frequency of 0.088 (8.8%) within the Polynesian sub-group and 0.035 (3.5%) across the wider group, including Melanesians and South Asians. In a genome sequencing dataset (low-pass sequencing followed by imputation), of participants of Aotearoa New Zealand Māori and Pacific Islander ancestry recruited to a Health and Disability study, the variant was present at an allele frequency of 4.0% in East Polynesian individuals (n=139), and 3.6% among West Polynesian individuals (n=55). Based on the ACMG/AMP guidelines, which consider a minor allele frequency over 0.05 as benign (BA1 criterion), we classify the variant as benign. Given that 16 ClinVar assertions report this as a variant of uncertain significance, this classification downgrade will have a clinically meaningful impact.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000159305	SCV005203394	uncertain significance	not specified	2024-07-18	criteria provided, single submitter	clinical testing	Variant summary: TNNT2 c.571-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' acceptor site. Two predict the variant creates a cryptic 3' acceptor site, and one predicts the variant strengthens a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, however it reports that the variant results in an in-frame deletion of one amino acid (Van Driest_2004), which is consistent with the computation predictions. The variant allele was found at a frequency of 2e-05 in 249022 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.571-1G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy or Dilated Cardiomyopathy without strong evidence of causality (e.g. Van Driest_2004, Rani_2014, Walsh_2017, McGurk_2023, Earle_2024). These reports do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. Co-occurrence with another pathogenic variant has been reported in one of these cases (MYH7 c.1357C>T, p.Arg453Cys), providing supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 15358028, 24992688, 27532257, 37652022, 38456273). ClinVar contains an entry for this variant (Variation ID: 132940). Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000223749	SCV005879496	uncertain significance	not provided	2024-08-22	criteria provided, single submitter	clinical testing	The TNNT2 c.571-1G>A variant (rs483352835, ClinVar Variation ID: 132940) is reported in the literature in several individuals affected with dilated cardiomyopathy and hypertrophic cardiomyopathy (Earle 2024, Mazzarotto 2020, McGurk 2023, Rani 2014, Walsh 2017). This variant has also been observed in individuals with hypertrophic cardiomyopathy that carried an additional variant that may explain the observed phenotype (Van Driest 2004, van Lint 2019). This variant is found in the South Asian population with an allele frequency of 0.016% (5/30,444 alleles) in the Genome Aggregation Database (v2.1.1). This variant disrupts the canonical splice acceptor site of intron 11, however, loss of function has not been established as a mechanism of disease. Due to limited information, the clinical significance of this variant is uncertain at this time. References: Earle NJ et al. Genetic Testing Yield and Clinical Characteristics of Hypertrophic Cardiomyopathy in Understudied Ethnic Groups: Insights From a New Zealand National Registry. Circ Heart Fail. 2024 Mar;17(3):e010970. PMID: 38456273. Mazzarotto F et al. Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy. Circulation. 2020 Feb 4;141(5):387-398. PMID: 31983221. McGurk KA et al. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. Am J Hum Genet. 2023 Sep 7;110(9):1482-1495. PMID: 37652022. Rani DS et al. A novel arginine to tryptophan (R144W) mutation in troponin T (cTnT) gene in an indian multigenerational family with dilated cardiomyopathy (FDCM). PLoS One. 2014 Jul 3;9(7):e101451. PMID: 24992688. Van Driest SL et al. Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004 Aug 4;44(3):602-10. PMID: 15358028. van Lint FHM et al. Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. Neth Heart J. 2019 Jun;27(6):304-309. PMID: 30847666. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257.
Evolutionary and Medical Genetics Laboratory, Centre for Cellular and Molecular Biology	RCV000119341	SCV000154238	unknown	Dilated cardiomyopathy 1DD		no assertion criteria provided	not provided	Converted during submission to Uncertain significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223749	SCV000280530	likely pathogenic	not provided	2010-09-30	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. IVS 11-1G>A. This variant changes the last base of the intron for a G to an A. This base is a key part of the splicing consensus sequence and is essentially always a G. Thus a change from G to A would be highly likely to affect splicing. Consistent with this expectation, Van Driest et al (2004) reported alternative splicing causing an in-frame deletion of a glutamine in a patient with this mutation. That patient also had a mutation in MYH7 (p.Arg453Cys) and a clinical history consistent with multiple mutations (infantile onset HCM with severe hypertrophy (38mm) and VT). While most TNNT2 mutations are missense, four other single amino acid deletions have been reported in association with HCM. No segregation data on this variant were reported by either the testing lab or Van Dreist et al. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~5300 Caucasian and African American individuals (as of 3/6/2012). Note that this dataset does not match the patient's ancestry (Samoan). Of note, there are no splicing variants in TNNT2 in this data set.
Clinical Genetics, Academic Medical Center	RCV000223749	SCV001978808	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000223749	SCV001979356	uncertain significance	not provided		no assertion criteria provided	clinical testing