ClinVar Miner

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

gnomAD frequency: 0.00061  dbSNP: rs200771189
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000724797 SCV000228518 uncertain significance not provided 2017-03-08 criteria provided, single submitter clinical testing
GeneDx RCV000724797 SCV000237614 likely benign not provided 2019-10-10 criteria provided, single submitter clinical testing
Invitae RCV000539580 SCV000643747 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive 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 benign Cardiomyopathy 2023-03-14 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 Center for Human Genetics Tuebingen RCV000724797 SCV001152722 likely benign not provided 2023-08-01 criteria provided, single submitter clinical testing TTN: BP4, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000259190 SCV001519583 likely benign not specified 2022-09-26 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 0.00035 in 248182 control chromosomes, predominantly at a frequency of 0.0006 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.54 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 Non-Finnish European origin. 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 2021-12-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV002345607 SCV002652895 likely benign Cardiovascular phenotype 2019-10-11 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity Omics RCV000724797 SCV003826653 likely benign not provided 2023-05-03 criteria provided, single submitter clinical testing
Clinical Genetics, Academic Medical Center RCV000724797 SCV001921433 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000724797 SCV001929807 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000724797 SCV001953609 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000724797 SCV001970705 likely benign not provided no assertion criteria provided clinical testing

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