Submissions for variant NM_001267550.2(TTN):c.72556A>G (p.Lys24186Glu)

gnomAD frequency: 0.00009  dbSNP: rs768699380

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184797	SCV000237512	uncertain significance	not specified	2014-10-02	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).
Mayo Clinic Laboratories, Mayo Clinic	RCV004791310	SCV005413037	uncertain significance	not provided	2024-08-12	criteria provided, single submitter	clinical testing	BP4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV004791310	SCV005878375	uncertain significance	not provided	2024-07-30	criteria provided, single submitter	clinical testing	The TTN c.72556A>G; p.Lys24186Glu variant (rs768699380; ClinVar Variation ID: 202841) 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.Lys24186Glu 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.