ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.55139T>C (p.Ile18380Thr)

gnomAD frequency: 0.00006  dbSNP: rs72646819
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Total submissions: 7
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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 RCV000040371 SCV000064062 uncertain significance not specified 2012-07-31 criteria provided, single submitter clinical testing The Ile15812Thr variant in TTN has been identified in 1/28 Spanish chromosomes a nd 1/196 Italian chromosomes from broad populations by the 1000 Genomes project (dbSNP rs72646819). The affected amino acid is not well conserved in evolution, suggesting that a change may be tolerated. Other computational analyses (biochem ical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide stron g support for or against an impact to the protein. Additional information is nee ded to fully assess the clinical significance of this variant.
GeneDx RCV000726968 SCV000237312 likely benign not provided 2020-11-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 30847666)
Labcorp Genetics (formerly Invitae), Labcorp RCV000555854 SCV000643373 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2017-06-06 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000726968 SCV000704566 uncertain significance not provided 2017-01-08 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000764327 SCV000895346 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000726968 SCV001152873 uncertain significance not provided 2023-11-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000040371 SCV001821374 uncertain significance not specified 2021-08-23 criteria provided, single submitter clinical testing Variant summary: TTN c.47435T>C (p.Ile15812Thr) results in a non-conservative amino acid change located in the A-band 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 7e-05 in 241606 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (7e-05 vs 0.00039), allowing no conclusion about variant significance. c.47435T>C has been reported in the literature in individuals affected with Dilated Cardiomyopathy, sudden cardiac death, unspecified cardiomyopathies, or Left Ventricular Non-Compaction (Pugh_2014, Campuzano_2015, vanLint_2019, Vershinina_2020). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has 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.

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