ClinVar Miner

Submissions for variant NM_133379.5(TTN):c.16516G>T (p.Glu5506Ter)

gnomAD frequency: 0.00004  dbSNP: rs148430495
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust RCV000209215 SCV000189802 uncertain significance Primary dilated cardiomyopathy 2014-10-08 criteria provided, single submitter research This TTN truncating variant (TTNtv) was identified in three individuals in this cohort. It affects only the Novex-3 isoform, which does not span the sarcomere and has not been implicated in DCM. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000152431 SCV000201484 uncertain significance not specified 2019-01-25 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Glu5506X variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 5/8598 of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs148430495). This variant is located in the last exon of an alternative transcript (Novex-3) and is expected to result in a truncated protein. Although truncating variants in the TTN gene are common in individuals with DCM (Herman 2012), the role of the Novex-3 transcript in cardiomyopathy is unclear. In summary, additional information is needed to fully assess the clinical significance of the Glu5506X variant.
Eurofins Ntd Llc (ga) RCV000730639 SCV000858390 uncertain significance not provided 2017-11-28 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001198154 SCV001368997 uncertain significance Tibial muscular dystrophy 2019-10-02 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: No criteria apply.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000152431 SCV002500821 uncertain significance not specified 2022-03-31 criteria provided, single submitter clinical testing Variant summary: TTN c.10360+7240G>T is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. Although this variant can also be interpreted as c.16516G>T/p.Glu5506X in NM_133379, the location of this variant is at the 3'-end of this transcript. In addition, this transcript is not expressed at high level in the DCM cohort or GTEx (https://www.cardiodb.org/titin). The variant allele was found at a frequency of 6.1e-05 in 246836 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Limb-Girdle Muscular Dystrophy, Type 2J, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.10360+7240G>T in individuals affected with Limb-Girdle Muscular Dystrophy, Type 2J and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Fulgent Genetics, Fulgent Genetics RCV002483320 SCV002794441 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 2021-09-08 criteria provided, single submitter clinical testing

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.