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

gnomAD frequency: 0.00010  dbSNP: rs397517662

Total submissions: 9

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, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Athena Diagnostics	RCV000993469	SCV001146462	uncertain significance	not provided	2024-02-07	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Computational tools predict that this variant is damaging.
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040496	SCV005422774	uncertain significance	not specified	2024-10-17	criteria provided, single submitter	clinical testing	Variant summary: TTN c.57968C>T (p.Pro19323Leu) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 246570 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Limb-Girdle Muscular Dystrophy, Type 2J, allowing no conclusion about variant significance. c.57968C>T has been reported in the literature in one individuals affected with Dilated cardiomyopathy, without strong evidence for causality (Burstein_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Type 2J. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32746448). ClinVar contains an entry for this variant (Variation ID: 47226). Based on the evidence outlined above, the variant was classified as uncertain significance.