Submissions for variant NM_001267550.2(TTN):c.103730A>G (p.Gln34577Arg)

gnomAD frequency: 0.00001  dbSNP: rs727505009

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156431	SCV000206149	uncertain significance	not specified	2014-03-05	criteria provided, single submitter	clinical testing	The Gln32009Arg variant in TTN has not been previously reported in individuals w ith cardiomyopathy or in large population studies. Computational prediction tool s and conservation analysis do not provide strong support for or against an impa ct to the protein. Additional information is needed to fully assess the clinical significance of the GLn32009Arg variant.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170291	SCV001332855	uncertain significance	Cardiomyopathy	2019-01-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001529352	SCV001779368	uncertain significance	not provided	2019-11-27	criteria provided, single submitter	clinical testing	Reported in a cohort of 639 patients with sporadic or familial DCM (Haas et al., 2015); of note, this variant is described as Q25704R due to the use of an alternate transcript; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 179636; Landrum et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 25163546)
Invitae	RCV001857542	SCV002131552	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 34577 of the TTN protein (p.Gln34577Arg). This variant is present in population databases (rs727505009, gnomAD 0.004%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 25163546). ClinVar contains an entry for this variant (Variation ID: 179636). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant is located in the M band of TTN (PMID: 25589632). Variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 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.
Fulgent Genetics, Fulgent Genetics	RCV002498767	SCV002778677	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	2021-10-07	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529352	SCV001742643	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001529352	SCV001921691	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529352	SCV001960001	uncertain significance	not provided		no assertion criteria provided	clinical testing