ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.601-373G>A (rs483352835)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000223749 SCV000209251 uncertain significance not provided 2018-07-25 criteria provided, single submitter clinical testing The c.571-1 G>A variant of uncertain significance in the TNNT2 gene has been identified in one individual with early onset, severe HCM who also harbored a pathogenic variant in the MYH7 gene, and in one individual with DCM (Van Driest et al., 2004; Rani et al., 2014). The c.571-1 G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant destroys the canonical splice acceptor site in intron 11 and is predicted to cause abnormal gene splicing. However, the majority of pathogenic variants in the TNNT2 gene are missense variants (Stenson et al., 2014), indicating that haploinsufficiency of TNNT2 may not be sufficient to cause cardiomyopathy.
Laboratory for Molecular Medicine,Partners HealthCare 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with cardiomyopathy (1 child DCM; 1 child LVNC; 1 child HCM and VT; 1 adult DCM) (Van Driest 2004, Rani 2014 , LMM unpublished data).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,; 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 Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2017-11-29 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 and likely results in an absent or disrupted protein product. This variant is present in population databases (rs483352835, ExAC 0.01%). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 24992688) and in several individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 27532257). However, in one of these individuals a pathogenic allele was also identified in a different gene, which suggests that this c.571-1G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 132940). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TNNT2 cause disease. 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.
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.

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