ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.59926C>T (p.His19976Tyr) (rs727503588)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000152270 SCV000201115 uncertain significance not specified 2014-05-01 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The His17408Tyr var iant in TTN has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this infor mation is not predictive enough to rule out pathogenicity. It should be noted th at several other species (armadillo, green seaturtle, painted turtle, and 5 fish es) carry a tyrosine (Tyr) at this position, suggesting that this change may be tolerated. This variant is located in the last three bases of the exon, which is part of the 5' splice region. Computational tools do not predict altered splici ng, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the His17408Tyr variant is uncert ain, the presence of this variant in other species suggests that it is more like ly to be benign.
GeneDx RCV000152270 SCV000237359 uncertain significance not specified 2013-09-30 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 mutations 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) The variant is found in DCM panel(s).
Invitae RCV000474565 SCV000542908 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2016-12-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618262 SCV000735257 likely benign Cardiovascular phenotype 2020-03-26 criteria provided, single submitter clinical testing In silico models in agreement (benign);Last nucleotide of exon;Other strong data supporting benign classification
Fulgent Genetics,Fulgent Genetics RCV000765563 SCV000896878 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Myopathy, early-onset, with fatal cardiomyopathy; Familial hypertrophic cardiomyopathy 9 2018-10-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000152270 SCV001160292 uncertain significance not specified 2019-03-01 criteria provided, single submitter clinical testing The c.52222C>T; p.His17408Tyr variant (rs727503588) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall frequency of 0.03 percent in the East Asian population (identified on 6 out of 19,198 chromosomes). This variant is directly 5' to a canonical donor splice site, and though a variant of this adjacent base has been reported in dilated cardiomyopathy, the c.52222C>T has not been reported. This missense variant affects a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical splice site. Without functional mRNA splicing however, the p.His17408Tyr variant cannot be classified with certainty.

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