ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.83281G>A (p.Val27761Ile) (rs371788070)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000040692 SCV000064383 likely benign not specified 2020-03-04 criteria provided, single submitter clinical testing The p.Val25193Ile variant in TTN is classified as likely benign because it has been identified in 0.03% (40/124946) of European chromosomes by gnomAD. ACMG/AMP Criteria applied: BS1.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000171313 SCV000228545 uncertain significance not provided 2018-08-30 criteria provided, single submitter clinical testing
GeneDx RCV000040692 SCV000237643 uncertain significance not specified 2017-10-18 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TTN gene. The V26120I variant (reported as V18696I due to the use of an alternate isoform) has been reported in association with hypertrophic cardiomyopathy (HCM) in a patient who also harbored additional cardiogenetic variants (Lopes et al., 2013). The V26120I variant is observed in 40/124946 (0.03%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). This substitution occurs at a position that is conserved across species, and in silico analysis suggests that this variant is probably damaging to the protein structure/function. However, the V26120I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Finally, this is a missense variant in a gene in which most reported pathogenic variants associated with cardiomyopathy are truncating/loss-of-function (Stenson et al., 2014).
Invitae RCV000466706 SCV000542346 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-12-08 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769925 SCV000901351 uncertain significance Cardiomyopathy 2017-10-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000040692 SCV001426796 uncertain significance not specified 2021-06-01 criteria provided, single submitter clinical testing Variant summary: TTN c.75577G>A (p.Val25193Ile) results in a conservative amino acid change located in the A-band region 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 0.00016 in 246350 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in TTN causing Cardiomyopathy (0.00016 vs 0.00063), allowing no conclusion about variant significance. c.75577G>A has been reported in the literature in an individual affected with hypertrophic cardiomyopathy who also carried a pathogenic MYBPC3 variant (c.1483C>G, p.Arg495Gly) (Lopes_2013). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287244 SCV001473915 uncertain significance none provided 2019-09-30 criteria provided, single submitter clinical testing The TTN c.83281G>A; p.Val27761Ile variant (rs371788070; ClinVar Variation ID: 47422) is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and has been reported in an individual with hypertrophic cardiomyopathy, although this individual also carried a pathogenic variant in a different gene (Lopes 2013). The clinical relevance of rare missense variants in the TTN gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Val27761Ile variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke and Hamdani. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. Lopes LR et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet. 2013 Apr;50(4):228-39.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000171313 SCV001502346 uncertain significance not provided 2020-07-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV001330312 SCV001521957 uncertain significance Dilated cardiomyopathy 1G 2020-01-21 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Developmental Genetics Unit,King Faisal Specialist Hospital & Research Centre RCV000171313 SCV000221510 likely pathogenic not provided no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.