ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.18172C>T (p.Arg6058Cys) (rs189127014)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185356 SCV000238249 likely benign not specified 2017-04-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000543023 SCV000642751 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-12-28 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726954 SCV000704421 uncertain significance not provided 2018-08-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000185356 SCV000710966 uncertain significance not specified 2016-05-27 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Arg4814Cys va riant in TTN has not been previously reported in individuals with cardiomyopathy , but has been identified in 0.1% (10/9720) of African chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs189127014) . Arginine (Arg) at position 4814 is not conserved in evolutionarily distant spe cies and 10 species of fish carry the variant cysteine (Cys), supporting that th is change may be tolerated. In summary, while the clinical significance of the p .Arg4814Cys variant is uncertain, these data suggest that it is more likely to b e benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000185356 SCV001519427 likely benign not specified 2021-03-15 criteria provided, single submitter clinical testing Variant summary: TTN c.14440C>T (p.Arg4814Cys) results in a non-conservative amino acid change located in the I-band domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 279664 control chromosomes, predominantly at a frequency of 0.0015 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 4 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.14440C>T 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=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

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