ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.55269G>C (p.Lys18423Asn)

gnomAD frequency: 0.00003  dbSNP: rs367799017
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
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 RCV000040373 SCV000064064 uncertain significance not specified 2012-06-28 criteria provided, single submitter clinical testing The Lys15855Asn variant (TTN) has not been previously reported in the literature . This variant has been identified by our laboratory in one proband with HCM. Th is variant has also been identified in 1/6608 European American chromosomes from a broad population sequenced by the NHLBI Exome Sequencing Project (http://evs. gs.washington.edu/EVS/). This frequency is too low to exclude a role in disease as this could represent a presymptomatic individual. This variant is located one base pair from the 5' splice region. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) predict that it m ay impact the protein and may also alter splicing, though this information is no t predictive enough to determine pathogenicity. In summary, the available data i s consistent with a pathogenic role but is insufficient to rule out a benign rol e. Additional studies are needed to fully assess the clinical significance of th is variant.
Invitae RCV000797680 SCV000937253 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2022-10-24 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 18423 of the TTN protein (p.Lys18423Asn). This variant also falls at the last nucleotide of exon 284, which is part of the consensus splice site for this exon. This variant is present in population databases (rs367799017, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 47103). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the A band of TTN (PMID: 25589632). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV003156220 SCV003845545 likely pathogenic not provided 2023-03-21 criteria provided, single submitter clinical testing Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge

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.