ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.58684A>G (p.Ile19562Val)

dbSNP: rs397517637
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000040408 SCV000064099 uncertain significance not specified 2015-03-21 criteria provided, single submitter clinical testing The p.Ile16994Val variant in TTN has been identified by our laboratory in 1 Cauc asian adult with DCM. It was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. Splicing prediction tools suggest this varian t may lead to the creation of a novel 5' splice site; however, this information is not predictive enough to determine pathogenicity. In summary, the clinical si gnificance of the p.Ile16994Val variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp RCV000643442 SCV000765129 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2017-10-11 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000770001 SCV000901427 uncertain significance Cardiomyopathy 2016-02-03 criteria provided, single submitter clinical testing
Genomic Medicine Lab, University of California San Francisco RCV001376061 SCV001573083 uncertain significance Hypertrophic cardiomyopathy 9 2020-12-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV002321521 SCV002608579 uncertain significance Cardiovascular phenotype 2018-09-13 criteria provided, single submitter clinical testing The p.I10497V variant (also known as c.31489A>G), located in coding exon 125 of the TTN gene, results from an A to G substitution at nucleotide position 31489. The isoleucine at codon 10497 is replaced by valine, an amino acid with highly similar properties. This exon is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This amino acid position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site; however, direct evidence is unavailable. 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.
Molecular Genetics, Royal Melbourne Hospital RCV003993765 SCV004812626 uncertain significance Primary dilated cardiomyopathy 2024-03-01 criteria provided, single submitter clinical testing This sequence change in TTN is predicted to replace isoleucine with valine at codon 19562, p.(Ile19562Val). The isoleucine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in constitutively expressed exon 298 (percentage splice in, PSI, 100%) in the A-band (PMID: 25589632). There is a small physicochemical difference between isoleucine and valine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.0005% (4/761,902 alleles) in the European (non-Finnish) population, which is consistent with dilated cardiomyopathy (DCM). This variant has been reported in at least one individual with DCM (PMID: 31983221). Computational evidence predicts an impact on splicing (SpliceAI) for the nucleotide change, and predicts a benign effect for the missense substitution (REVEL = 0.12). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3.
PreventionGenetics, part of Exact Sciences RCV004734569 SCV005365360 uncertain significance TTN-related disorder 2024-08-20 no assertion criteria provided clinical testing The TTN c.58684A>G variant is predicted to result in the amino acid substitution p.Ile19562Val. This variant has been reported in the homozygous state as a variant of uncertain significance in an individual with dilated cardiomyopathy who also carried additional variants in MYBPC3 and TTN (Reported as c.50980A>G with NM_133378.4 in Case #299 in Supp. Table 1 in Pugh TJ et al. 2014. PubMed ID: 24503780). In addition, this variant is predicted to create a strong donor splice site signal within the exon and may result in aberrant splicing (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). However, the use of computer prediction programs is not equivalent to functional evidence. To our knowledge, this variant has not been reported in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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.