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

dbSNP: rs371788070

Total submissions: 13

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.
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	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)
Invitae	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