ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.26528C>T (p.Thr8843Met)

gnomAD frequency: 0.00032  dbSNP: rs72648990
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000040052 SCV000063743 uncertain significance not specified 2017-06-28 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Thr7599Met va riant in TTN has been identified by our laboratory in 1 Asian adult with HCM, 1 Ethiopian neonate with congenital HCM, and 2 Caucasian adults with DCM, of which 1 carried a likely pathogenic variant in another gene sufficient to explain the ir disease (Pugh 2014). Additionally, this variant has been identified in 0.1% ( 38/34342) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org/; dbSNP rs72648990) and has been reported in ClinVa r (Variation ID: 46782). Threonine (Thr) at position 7599 is not conserved in ma mmals or evolutionarily distant species, and one mammal (white rhinoceros) carri es a methionine (Met) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools do not provide stro ng support for or against an impact to the protein. In summary, while the clinic al significance of the p.Thr7599Met variant is uncertain, its frequency and lack of conservation suggest that it is more likely to be benign.
GeneDx RCV000725012 SCV000238377 likely benign not provided 2021-02-22 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24503780, 27066507)
Invitae RCV000226309 SCV000286538 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2017-08-22 criteria provided, single submitter clinical testing
Eurofins NTD LLC (GA) RCV000725012 SCV000333200 uncertain significance not provided 2018-07-03 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000714648 SCV000845366 uncertain significance TTN-Related Disorders 2018-08-07 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000725012 SCV001146357 likely benign not provided 2019-12-30 criteria provided, single submitter clinical testing
Genetics and Genomics Program,Sidra Medicine RCV001293146 SCV001434136 uncertain significance Hypertrophic cardiomyopathy criteria provided, single submitter research
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000725012 SCV002049659 uncertain significance not provided 2021-02-24 criteria provided, single submitter clinical testing The TTN c.26528C>T; p.Thr8843Met variant (rs72648990; ClinVar Variation ID: 46782) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Given the available evidence, the clinical significance of the p.Thr8843Met variant cannot be determined with certainty.

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