ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.55374C>G (p.Ser18458Arg) (rs200550947)

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Total submissions: 7
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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 RCV000172660 SCV000054983 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000152301 SCV000201168 uncertain significance not specified 2014-08-27 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Ser15890Arg var iant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.1% (10/8194) of European American chromosomes by t he NHLBI Exome Sequencing Project (; dbSNP rs20 0550947). Computational prediction tools and conservation analysis do not provid e strong support for or against an impact to the protein. In summary, while the clinical significance of the Ser15890Arg variant is uncertain, its frequency sug gests that it is more likely to be benign.
GeneDx RCV000172660 SCV000237316 likely benign not provided 2020-10-05 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23861362)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000172660 SCV000333474 uncertain significance not provided 2015-07-31 criteria provided, single submitter clinical testing
Invitae RCV000476468 SCV000542339 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-12-29 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000172660 SCV001152871 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000152301 SCV001821441 likely benign not specified 2021-08-30 criteria provided, single submitter clinical testing Variant summary: TTN c.47670C>G (p.Ser15890Arg) results in a non-conservative amino acid change located in the A-band domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 277010 control chromosomes, predominantly at a frequency of 0.0007 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 2 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.47670C>G has been reported in the literature in one individual affected with Dilated Cardiomyopathy (Roggenbuck_2019). The report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Additionally, one co-occurrence with another pathogenic variant has been reported (exons 346-362 deletion; Roggenbuck_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has 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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