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

gnomAD frequency: 0.00004  dbSNP: rs148430495

Total submissions: 6

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	2025-01-16	criteria provided, single submitter	clinical testing	Variant summary: TTN NM_133378:c.10360+7240G>T is located at a position not widely known to affect splicing. This variant corresponds to c.11312-3963G>T in NM_001267550 and NM_133379:c.16516G>T p.Glu5506X, however nonsense mediated decay is not expected. Loss of function variants in all TTN bands are strongly associated with a spectrum of autosomal recessive titinopathies when exon expression (proportion spliced in, PSI, 1=complete expression) in skeletal muscle is >0.1 (PMID: 36977548, 39198997, 29598826, 32778822, 29691892, 33449170, 36977548, internal data). In contrast, loss of function variants in all TTN bands are only strongly associated with autosomal dominant TTN-related cardiomyopathies if located in exons constitutively expressed (PSI >0.9) in cardiac muscle, excluding extreme C-terminal exons 359-363 (PMID: 25589632, 31216868, 32964742, 34662387, 27869827, Shetty et al., Nat Cardiovasc Res 2024, cardiodb.org, internal data). This variant has a maximum skeletal muscle PSI of 0.02 and a maximum cardiac muscle PSI of 0.035. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.4e-05 in 330022 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Autosomal Recessive Titinopathy (6.4e-05 vs 0.00039), allowing no conclusion about variant significance. c.10360+7240G>T has been reported in the literature in individuals affected with clinical features of cardiomyopathy without strong evidence for causality (Jurgens_2022) and wad not enriched in the Atrial Fibrillation cohort from the UK Biobank (Connell_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Titinopathy and other TTN-related diseaes. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31691645, 35177841, 33226272). ClinVar contains an entry for this variant (Variation ID: 166247). Based on the evidence outline above, and the lack of clinical evidence in a low PSI exon, the variant has been classified as uncertain significance.
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