Submissions for variant NM_001267550.2(TTN):c.9472G>T (p.Val3158Phe)

gnomAD frequency: 0.00002  dbSNP: rs748114137

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000621913	SCV000737068	uncertain significance	Cardiovascular phenotype	2016-02-12	criteria provided, single submitter	clinical testing	The p.V3112F variant (also known as c.9334G>T) is located in coding exon 39 of the TTN gene. The valine at codon 3112 is replaced by phenylalanine, an amino acid with highly similar properties. This change occurs in the first base pair of exon 40 which makes it likely to have some effect on normal mRNA splicing. Based on data from ExAC, the T allele was reported in 1 of 120294 (0.0008%) total alleles (Exome Aggregation Consortium (ExAC), Cambridge, MA (URL: http://exac.broadinstitute.org) [Accessed February 11, 2016]). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice acceptor site; however, direct experimental evidence is unavailable. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
AiLife Diagnostics, AiLife Diagnostics	RCV002223882	SCV002503081	uncertain significance	not provided	2021-12-03	criteria provided, single submitter	clinical testing
GeneDx	RCV002223882	SCV003195238	uncertain significance	not provided	2022-07-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing; however, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; Has not been previously published as pathogenic or benign to our knowledge
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002223882	SCV005879470	uncertain significance	not provided	2024-08-20	criteria provided, single submitter	clinical testing	The TTN c.9472G>T; p.Val3158Phe variant (rs748114137), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 519086). This variant is found in the non-Finnish European population with an allele frequency of 0.003% (3/112,762 alleles) in the Genome Aggregation Database (v2.1.1). This variant occurs in the first nucleotide of exon 41, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site, although RNA studies would be required to confirm this. Given the lack of clinical and functional data, the significance of this variant is uncertain at this time.