ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.81472C>G (p.Pro27158Ala) (rs200771189)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724797 SCV000228518 uncertain significance not provided 2017-03-08 criteria provided, single submitter clinical testing
GeneDx RCV000259190 SCV000237614 likely benign not specified 2017-07-11 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 RCV000539580 SCV000643747 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-12-19 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000724797 SCV000884809 likely benign not provided 2018-06-20 criteria provided, single submitter clinical testing The c.73768C>G; p.Pro24590Ala variant does not alter the amino acid sequence of the TTN protein and computational splice site prediction algorithms do not predict a change in the nearest splice site or creation of a cryptic splice site. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.04 % (identified on 115 out of 276,066 chromosomes), and evidence suggests that the vast majority of rare non-truncating TTN variants do not contribute to the clinical outcome of DCM (Begay 2015). Given the available evidence, the c.73768C>G variant is likely to be benign. This variant was detected in an unaffected individual who was an obligate heterozygote for Barth syndrome and in whom a pathogenic TAZ variant was detected. Thus, this TTN variant is considered likely benign.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769926 SCV000901352 uncertain significance Cardiomyopathy 2017-08-15 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000724797 SCV001146507 likely benign not provided 2019-03-13 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000724797 SCV001152722 likely benign not provided 2017-02-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000259190 SCV001519583 likely benign not specified 2021-03-01 criteria provided, single submitter clinical testing Variant summary: TTN c.73768C>G (p.Pro24590Ala) results in a non-conservative amino acid change located in the A-band region 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 0.00041 in 279582 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is higher than the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy (DCM) phenotype (0.00039), strongly suggesting that the variant is benign. c.73768C>G has been reported in the literature in individuals affected with hypertrophic cardiomyopathy (Lopes_2013) and Brugada syndrome, but without echocardiographic evidence for structural heart disease (Mademont-Soler_2017). These reports do not provide unequivocal conclusions about association of the variant with DCM. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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 VUS (n=3) or likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000724797 SCV001714638 uncertain significance not provided 2021-03-24 criteria provided, single submitter clinical testing

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