Submissions for variant NM_001267550.2(TTN):c.42950G>A (p.Arg14317Gln)

dbSNP: rs727505144

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156610	SCV000206330	uncertain significance	not specified	2014-06-19	criteria provided, single submitter	clinical testing	The Arg11749Gln 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, though 2 mammals (dolphin and killer whale) have a glutamine (Glu) at this position, raising the possibility that this change may be tolerate d. In summary, the clinical significance of the Arg11749Gln variant is uncertain .
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001562713	SCV001470834	uncertain significance	not provided	2019-09-30	criteria provided, single submitter	clinical testing	The TTN c.42950G>A; p.Arg14317Gln variant (rs727505144; ClinVar Variation ID: 179811) is rare in the general population (<1% 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.Arg14317Gln variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke and Hamdani. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068.
GeneDx	RCV001562713	SCV001785521	uncertain significance	not provided	2020-12-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399559	SCV002709449	uncertain significance	Cardiovascular phenotype	2019-08-30	criteria provided, single submitter	clinical testing	The p.R5252Q variant (also known as c.15755G>A), located in coding exon 60 of the TTN gene, results from a G to A substitution at nucleotide position 15755. The arginine at codon 5252 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.