ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.25481G>A (p.Arg8494Gln) (rs201418615)

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Total submissions: 6
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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 RCV000172687 SCV000055047 likely benign not provided 2013-06-24 criteria provided, single submitter research
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000172687 SCV000232857 uncertain significance not provided 2014-08-29 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000215717 SCV000272603 uncertain significance not specified 2015-07-29 criteria provided, single submitter clinical testing The p.Arg7250Gln variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.15% (15/9798) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs201418615). Computational prediction tools and conservation analysis d o not provide strong support for or against an impact to the protein. In summary , the clinical significance of the p.Arg7250Gln variant is uncertain.
Invitae RCV001083467 SCV000555448 likely benign Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-11-22 criteria provided, single submitter clinical testing
GeneDx RCV000215717 SCV000714643 likely benign not specified 2017-07-07 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000215717 SCV001431968 likely benign not specified 2020-08-24 criteria provided, single submitter clinical testing Variant summary: TTN c.21749G>A (p.Arg7250Gln) results in a conservative amino acid change located in the I-band domain 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 0.0002 in 280342 control chromosomes, predominantly at a frequency of 0.0022 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 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.21749G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One co-occurrence with another pathogenic variant has been internally reported (TTR c.424G>A, p.V142I), providing supporting evidence for a benign role. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.

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