Submissions for variant NM_001267550.2(TTN):c.57262G>T (p.Val19088Phe)

gnomAD frequency: 0.00001  dbSNP: rs727505347

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156902	SCV000206623	uncertain significance	not specified	2014-11-24	criteria provided, single submitter	clinical testing	The p.Val16520Phe variant in TTN has not been previously reported in individuals with cardiomyopathy and was absent from large population studies. This variant is located in the last three bases of the exon, which is part of the 5? splice r egion. Computational tools suggest an impact to splicing; however, this informat ion is not predictive enough to determine pathogenicity. In summary, the clinica l significance of the p.Val16520Phe variant is uncertain.
GeneDx	RCV000156902	SCV000237330	uncertain significance	not specified	2013-05-09	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 DCM panel(s).
Invitae	RCV001850173	SCV002138023	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-03-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine with phenylalanine at codon 19088 of the TTN protein (p.Val19088Phe). There is a small physicochemical difference between valine and phenylalanine. This variant also falls at the last nucleotide of exon 293, which is part of the consensus splice site for this exon. This variant is present in population databases (rs727505347, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 180098). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the A band of TTN (PMID: 25589632). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002478467	SCV002784553	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-09-20	criteria provided, single submitter	clinical testing