Submissions for variant NM_001267550.2(TTN):c.54167G>A (p.Arg18056Gln)

gnomAD frequency: 0.00005  dbSNP: rs376932266

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040354	SCV000064045	uncertain significance	not specified	2017-01-31	criteria provided, single submitter	clinical testing	The p.Arg15488Gln variant in TTN has been identified in one infant with DCM who also carried a likely pathogenic variant in VCL (LMM data). It has been identifi ed in 2/65398 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs376932266). Computational prediction to ols and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg15488Gln variant is uncertain.
Invitae	RCV000553724	SCV000643356	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-06-28	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000993454	SCV001146433	uncertain significance	not provided	2018-09-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000993454	SCV002541946	uncertain significance	not provided	2021-10-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477120	SCV002776907	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	2021-10-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040354	SCV002819860	uncertain significance	not specified	2022-12-27	criteria provided, single submitter	clinical testing	Variant summary: TTN c.46463G>A (p.Arg15488Gln) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 239712 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.46463G>A has been reported in the literature in an individual affected with Dilated Cardiomyopathy, however other potentially causative co-occurring variants were also identified in this patient (Pugh_2014). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000993454	SCV004562340	uncertain significance	not provided	2023-01-03	criteria provided, single submitter	clinical testing	The TTN c.54167G>A; p.Arg18056Gln variant (rs376932266; ClinVar Variation ID: 47084) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this 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.Arg18056Gln variant cannot be determined with certainty.
CeGaT Center for Human Genetics Tuebingen	RCV000993454	SCV004699732	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	TTN: PM2:Supporting, BP4