ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.44077C>T (p.Arg14693Cys) (rs200445568)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724241 SCV000226858 uncertain significance not provided 2014-10-23 criteria provided, single submitter clinical testing
GeneDx RCV000724241 SCV000237172 likely benign not provided 2020-10-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000219227 SCV000272647 uncertain significance not specified 2015-01-28 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Arg12125Cys v ariant in TTN has not been previously reported in individuals with cardiomyopath y, but has been identified in 0.2% (20/9970) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200445568 ). Computational prediction tools and conservation analysis suggest that this va riant may impact the protein, though this information is not predictive enough t o determine pathogenicity. In summary, while the clinical significance of the p. Arg12125Cys variant is uncertain, its frequency suggests that it is more likely to be benign.
Invitae RCV001079420 SCV000555130 likely benign Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-11-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618077 SCV000737338 likely benign Cardiovascular phenotype 2018-12-05 criteria provided, single submitter clinical testing Insufficient evidence;Other strong data supporting benign classification;Subpopulation frequency in support of benign classification
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769015 SCV000900388 uncertain significance Cardiomyopathy 2016-06-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000219227 SCV001448485 likely benign not specified 2020-11-16 criteria provided, single submitter clinical testing Variant summary: TTN c.36373C>T (p.Arg12125Cys) results in a non-conservative amino acid change located in the I-band domain 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 0.00023 in 279870 control chromosomes, predominantly at a frequency of 0.0024 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. c.36373C>T has been reported in the literature in one individual affected with sudden cardiac death (Campuzano_2018). The report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (2x) and likely benign (3x). Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Genetics,Academic Medical Center RCV000724241 SCV001920264 likely benign not provided no assertion criteria provided clinical testing

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