ClinVar Miner

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

dbSNP: rs371788070
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000040692 SCV000064383 likely benign not specified 2022-06-30 criteria provided, single submitter clinical testing Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: . ACMG Criteria applied: BS1.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000171313 SCV000221510 likely pathogenic not provided criteria provided, single submitter research
Eurofins Ntd Llc (ga) RCV000171313 SCV000228545 uncertain significance not provided 2018-08-30 criteria provided, single submitter clinical testing
GeneDx RCV000171313 SCV000237643 likely benign not provided 2020-06-11 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23396983)
Labcorp Genetics (formerly Invitae), Labcorp RCV000466706 SCV000542346 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive 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 RCV000171313 SCV001473915 uncertain significance not 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 Center for Human Genetics Tuebingen RCV000171313 SCV001502346 uncertain significance not provided 2023-12-01 criteria provided, single submitter clinical testing TTN: PM2
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].
Genetic Services Laboratory, University of Chicago RCV000040692 SCV002067928 uncertain significance not specified 2017-11-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV002345321 SCV002648357 uncertain significance Cardiovascular phenotype 2019-04-19 criteria provided, single submitter clinical testing The p.V18696I variant (also known as c.56086G>A), located in coding exon 153 of the TTN gene, results from a G to A substitution at nucleotide position 56086. The valine at codon 18696 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity RCV000171313 SCV003826745 uncertain significance not provided 2023-02-22 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004734575 SCV005366626 uncertain significance TTN-related disorder 2024-09-04 no assertion criteria provided clinical testing The TTN c.83281G>A variant is predicted to result in the amino acid substitution p.Val27761Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.032% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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