ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.62432A>G (p.Asp20811Gly) (rs72646849)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184692 SCV000237387 likely benign not specified 2017-12-28 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.
Ambry Genetics RCV000251314 SCV000320405 likely benign Cardiovascular phenotype 2018-05-14 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000184692 SCV000710953 likely benign not specified 2016-08-14 criteria provided, single submitter clinical testing p.Asp18243Gly in exon 253 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.3% (26/9798) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs72646849).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727721 SCV000855076 uncertain significance not provided 2018-05-25 criteria provided, single submitter clinical testing
Invitae RCV001079582 SCV001012298 likely benign Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-12-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000184692 SCV001519571 likely benign not specified 2021-03-15 criteria provided, single submitter clinical testing Variant summary: TTN c.54728A>G (p.Asp18243Gly) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 248564 control chromosomes, predominantly at a frequency of 0.0026 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 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.54728A>G in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (n=4), or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

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