ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.61409T>C (p.Ile20470Thr)

gnomAD frequency: 0.00022  dbSNP: rs202012910
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Total submissions: 11
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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 RCV000040443 SCV000064134 uncertain significance not specified 2012-11-07 criteria provided, single submitter clinical testing The Ile17902Thr variant in TTN has not been reported in the literature nor previ ously identified by our laboratory. This variant has been identified in 2/8304 E uropean American chromosomes and 2/3916 African American chromosomes from a broa d population by the NHLBI Exome Sequencing Project ( /EVS). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional information is needed to fully ass ess the variant's clinical significance.
Genetic Services Laboratory,University of Chicago RCV000118773 SCV000153317 uncertain significance not provided 2014-01-10 criteria provided, single submitter clinical testing
GeneDx RCV000118773 SCV000237376 likely benign not provided 2019-12-24 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28152038)
Eurofins NTD LLC (GA) RCV000118773 SCV000706525 uncertain significance not provided 2017-02-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621098 SCV000736103 likely benign Cardiovascular phenotype 2020-05-20 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV000643646 SCV000765333 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2017-12-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000040443 SCV001362822 uncertain significance not specified 2019-11-11 criteria provided, single submitter clinical testing Variant summary: TTN c.53705T>C (p.Ile17902Thr) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 213576 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00011 vs 0.00063), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.53705T>C in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000118773 SCV002506224 uncertain significance not provided 2022-02-08 criteria provided, single submitter clinical testing The TTN c.61409T>C; p.Ile20470Thr variant (rs202012910; ClinVar Variation ID: 47173) 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). Thus, the clinical significance of the p.Ile20470Thr variant cannot be determined with certainty.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000118773 SCV001554280 uncertain significance not provided no assertion criteria provided clinical testing The TTN p.I17902T variant was not identified in the literature but was identified in dbSNP (ID: rs202012910) and ClinVar (classified as uncertain significance by Invitae, GeneDx and five other laboratories). The variant was identified in control databases in 30 of 244940 chromosomes at a frequency of 0.0001225 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.I17902 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000118773 SCV001952517 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000118773 SCV001969476 uncertain significance not provided no assertion criteria provided clinical testing

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