ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.75361A>G (p.Ile25121Val) (rs199508062)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000727705 SCV000237545 likely benign not provided 2020-09-25 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000217890 SCV000271077 likely benign not specified 2015-10-31 criteria provided, single submitter clinical testing p.Ile22553Val in exon 275 of TTN: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, >10 mammals have a valine (Val) at this position despite high nearby amin o acid conservation. It has been identified in 0.1% (13/9804) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199508062).
Invitae RCV001088038 SCV000643670 likely benign Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-11-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727705 SCV000855051 uncertain significance not provided 2018-08-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000217890 SCV001478818 likely benign not specified 2021-01-28 criteria provided, single submitter clinical testing Variant summary: TTN c.67657A>G (p.Ile22553Val) results in a conservative amino acid change located in the A-band domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 248426 control chromosomes, predominantly at a frequency of 0.001 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.67657A>G in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.

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