ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.57212T>C (p.Ile19071Thr) (rs200001206)

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Total submissions: 7
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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 RCV000154063 SCV000054980 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000040388 SCV000064079 uncertain significance not specified 2012-05-31 criteria provided, single submitter clinical testing The Ile16503Thr variant in TTN has been identified in 1/3071 African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS). This frequency is insufficient to rule out pathogeni city as this may have been a presymptomatic individual. Isoleucine (Ile) at posi tion 16503 is not well conserved in evolution, suggesting that a change may be t olerated though this is not predictive enough to rule out pathogenicity. Other computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein . Additional information is needed to fully assess the clinical significance of the Ile16503Thr variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000154063 SCV000203704 uncertain significance not provided 2018-05-10 criteria provided, single submitter clinical testing
Invitae RCV000456245 SCV000542926 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-09-25 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000154063 SCV001146441 likely benign not provided 2019-05-29 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000154063 SCV001249871 uncertain significance not provided 2020-01-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000040388 SCV001426965 uncertain significance not specified 2020-07-06 criteria provided, single submitter clinical testing Variant summary: TTN c.49508T>C (p.Ile16503Thr) results in a non-conservative amino acid change located in the A-band region (cardiodb.org) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 248686 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Cardiomyopathy (0.00032 vs 0.00063), allowing no conclusion about variant significance. c.49508T>C has been reported in the literature in at least one patient evaluated for sudden cardiac death (Hertz_2016). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function have been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

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