ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.21548G>A (p.Cys7183Tyr) (rs189951108)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172692 SCV000051259 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154980 SCV000204662 uncertain significance not specified 2017-09-12 criteria provided, single submitter clinical testing The p.Cys5939Tyr variant in TTN has been identified by our laboratory in 1 indiv idual with RCM and 1 with HCM; however, both individuals harbor pathogenic varia nts in other genes responsible for their symptoms. This variant has been identif ied in 76/126152 of European chromosomes by the Genome Aggregation Database (gno mAD, http://gnomad.broadinstitute.org/; dbSNP rs189951108) and has been reported in ClinVar (Variation ID: 178242). Computational prediction tools and conservat ion analysis suggest that the p.Cys5939Tyr variant may impact the protein, thoug h this information is not predictive enough to determine pathogenicity. In summa ry, the clinical significance of the p.Cys5939Tyr variant is uncertain.
GeneDx RCV000154980 SCV000238297 uncertain significance not specified 2017-05-17 criteria provided, single submitter clinical testing Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating variants in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000172692 SCV000336057 uncertain significance not provided 2018-01-19 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000172692 SCV000493407 uncertain significance not provided 2016-08-31 criteria provided, single submitter clinical testing
Invitae RCV000473052 SCV000542602 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-11-17 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000172692 SCV000844640 likely benign not provided 2019-01-10 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852895 SCV000995631 likely benign Arrhythmogenic right ventricular cardiomyopathy 2019-04-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000154980 SCV001159319 uncertain significance not specified 2018-09-25 criteria provided, single submitter clinical testing The TTN c.17816G>A; p.Cys5939Tyr variant (rs189951108; ClinVar Variation ID: 178242) is rare in the general population (<1% 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). Thus, the clinical significance of the p.Cys5939Tyr variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170082 SCV001332621 likely benign Cardiomyopathy 2018-05-24 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000172692 SCV001713248 uncertain significance not provided 2020-12-30 criteria provided, single submitter clinical testing

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