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

gnomAD frequency: 0.00001  dbSNP: rs483352835

Total submissions: 16

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with cardiomyopathy (1 child DCM; 1 child LVNC; 1 child HCM and VT; 1 adult DCM) (Van Driest 2004, Rani 2014 , LMM unpublished data).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.
Invitae	RCV000475521	SCV000541924	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-09	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). 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	uncertain significance	Cardiomyopathy	2022-12-06	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. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in three individuals affected with dilated cardiomyopathy (PMID: 24992688, 31983221) and in several individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 27532257, 30847666). One of the individuals affected with hypertrophic cardiomyopathy carried a pathogenic p.Arg453His in the MYH7 gene that could explain the observed phenotype. 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.
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	2023-01-09	criteria provided, single submitter	clinical testing	The c.571-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 11 of the TNNT2 gene. This alteration has been reported in cardiomyopathy cohorts; however, clinical details were limited and additional alterations in cardiac-related genes were identified in some cases (Van Driest SL et al. J Am Coll Cardiol, 2004 Aug;44:602-10; Rani DS et al. PLoS One, 2014 Jul;9:e101451; Walsh R et al. Genet Med, 2017 02;19:192-203). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, loss of function of TNNT2 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003225029	SCV003921918	uncertain significance	Dilated cardiomyopathy 1D	2021-05-07	criteria provided, single submitter	clinical testing	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, e.g., the variant, 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) and once as likely pathogenic (ClinVar). 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 <i>MYH7</i> gene (PMID: 15358028). Although 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 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
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