Submissions for variant NM_001267550.2(TTN):c.12889T>G (p.Cys4297Gly)

gnomAD frequency: 0.00013  dbSNP: rs377063950

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152418	SCV000201452	uncertain significance	not specified	2013-08-30	criteria provided, single submitter	clinical testing	The Cys4059Gly variant in TTN has not been previously reported in individuals wi th cardiomyopathy, but has been identified in 1/8244 European American chromosom es by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbS NP rs377063950). Computational analyses are limited or unavailable for this vari ant. Additional studies are need to fully assess the clinical significance of th is variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000643407	SCV000765094	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2025-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326875	SCV002633469	uncertain significance	Cardiovascular phenotype	2019-06-19	criteria provided, single submitter	clinical testing	The p.C3934G variant (also known as c.11800T>G), located in coding exon 44 of the TTN gene, results from a T to G substitution at nucleotide position 11800. The cysteine at codon 3934 is replaced by glycine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species, and glycine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001358499	SCV003800005	uncertain significance	not provided	2022-06-28	criteria provided, single submitter	clinical testing	The TTN NM_001267550.2: c.12889T>G; p.Cys4297Gly variant (rs377063950; ClinVar Variation ID: 166235) 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.Cys4297Gly variant cannot be determined with certainty.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358499	SCV001554249	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TTN p.Cys4059Gly variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs377063950) and ClinVar (classified as uncertain significance by Laboratory for Molecular Medicine and as likely benign by Invitae). The variant was identified in control databases in 28 of 248276 chromosomes at a frequency of 0.000113 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 20 of 10040 chromosomes (freq: 0.001992), Latino in 4 of 34446 chromosomes (freq: 0.000116) and European (non-Finnish) in 4 of 112328 chromosomes (freq: 0.000036), but was not observed in the African, East Asian, European (Finnish), Other, or South Asian populations. The p.Cys4059 residue has limited species conservation data and computational analyses (PolyPhen-2, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.