Submissions for variant NM_001267550.2(TTN):c.10922T>C (p.Ile3641Thr)

gnomAD frequency: 0.00045  dbSNP: rs141027782

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041118	SCV000064809	likely benign	not specified	2012-12-18	criteria provided, single submitter	clinical testing	Ile3470Thr in exon 44B of TTN: This variant is not expected to have clinical sig nificance because it has been identified in 2.6% (5/192) of Luhya chromosomes fr om a broad population by the 1000 Genomes project (dbSNP rs141027782). Ile3470T hr in exon 44B of TTN (rs141027782; allele frequency = 2.6%, 5/192)
GeneDx	RCV000041118	SCV000238082	uncertain significance	not specified	2015-12-01	criteria provided, single submitter	clinical testing	Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in CARDIOMYOPATHY panel(s).
Invitae	RCV001088266	SCV000555226	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000462754	SCV001153153	uncertain significance	not provided	2016-06-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000462754	SCV003799863	uncertain significance	not provided	2022-09-20	criteria provided, single submitter	clinical testing	The TTN c.10922T>C; p.Ile3641Thr variant (rs141027782; ClinVar Variation ID: 47849) 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.Ile3641Thr 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). PMID: 26567375. Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. PMID: 22335739. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. PMID: 24625729.