Submissions for variant NM_001267550.2(TTN):c.65672C>T (p.Pro21891Leu)

gnomAD frequency: 0.00010  dbSNP: rs397517662

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040496	SCV000064187	uncertain significance	not specified	2012-10-08	criteria provided, single submitter	clinical testing	The Pro19323Leu variant in TTN has not been reported in the literature nor previ ously identified by our laboratory. Computational analyses (biochemical amino ac id properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide stro ng support for or against an impact to the protein. Additional information is n eeded to fully assess the clinical significance of the Pro19323Leu variant.
Ambry Genetics	RCV000252626	SCV000320571	uncertain significance	Cardiovascular phenotype	2018-08-17	criteria provided, single submitter	clinical testing	The p.P12826L variant (also known as c.38477C>T), located in coding exon 140 of the TTN gene, results from a C to T substitution at nucleotide position 38477. The proline at codon 12826 is replaced by leucine, an amino acid with 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 variant remains unclear.
Athena Diagnostics Inc	RCV000993469	SCV001146462	uncertain significance	not provided	2018-08-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000993469	SCV001152804	likely benign	not provided	2018-10-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000993469	SCV001472126	uncertain significance	not provided	2019-09-04	criteria provided, single submitter	clinical testing	The TTN c.65672C>T, p.Pro21891Leu variant (rs397517662; ClinVar Variation ID: 47226) 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.Pro21891Leu 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.
Baylor Genetics	RCV001329655	SCV001521150	uncertain significance	Myopathy, myofibrillar, 9, with early respiratory failure	2019-05-21	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Baylor Genetics	RCV001329656	SCV001521151	uncertain significance	Dilated cardiomyopathy 1G	2020-07-09	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000993469	SCV003824801	uncertain significance	not provided	2021-03-22	criteria provided, single submitter	clinical testing