Submissions for variant NM_001267550.2(TTN):c.14309A>G (p.Tyr4770Cys)

gnomAD frequency: 0.00010  dbSNP: rs371552518

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152409	SCV000201434	uncertain significance	not specified	2015-06-10	criteria provided, single submitter	clinical testing	The p.Tyr3526Cys variant in TTN has been identified by our laboratory in 1 Cauca sian adult with DCM. It has also been identified in 13/66560 European chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs371552518). Computational prediction tools and conservation analysis do no t provide strong support for or against an impact to the protein. In summary, th e clinical significance of the p.Tyr3526Cys variant is uncertain.
GeneDx	RCV000152409	SCV000238196	uncertain significance	not specified	2016-08-15	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,CARDIOMYOPATHY panel(s).
Invitae	RCV000473338	SCV000542453	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-11	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000726956	SCV000704426	uncertain significance	not provided	2016-12-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000726956	SCV002048962	uncertain significance	not provided	2021-04-14	criteria provided, single submitter	clinical testing	The TTN c.14309A>G; p.Tyr4770Cys variant (rs371552518; ClinVar Variation ID: 166226) 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.Tyr4770Cys 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). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068.
Mayo Clinic Laboratories, Mayo Clinic	RCV000726956	SCV002541981	uncertain significance	not provided	2021-11-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000152409	SCV002547641	uncertain significance	not specified	2022-05-17	criteria provided, single submitter	clinical testing	Variant summary: TTN c.10577A>G (p.Tyr3526Cys) results in a non-conservative amino acid change located in the I-Band of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 248660 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.0001 vs 0.00039), allowing no conclusion about variant significance. c.10577A>G has been reported in the literature in individuals affected with Dilated Cardiomyopathy or suspected neuromuscular disorder (Wasielewski_2014, Westra_2019, Verdonschot_2020). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002381480	SCV002690442	uncertain significance	Cardiovascular phenotype	2018-10-31	criteria provided, single submitter	clinical testing	The p.Y4407C variant (also known as c.13220A>G), located in coding exon 45 of the TTN gene, results from an A to G substitution at nucleotide position 13220. The tyrosine at codon 4407 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant, reported as p.Y4453C ( c.13358A>G), was detected in conjunction with other cardiac related variants in a proband with anthracycline-associated cardiomyopathy (Wasielewski M. Open Heart. 2014 Jul;1(1):e000116). This amino acid position is highly conserved in available vertebrate species. 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.
Fulgent Genetics, Fulgent Genetics	RCV002505157	SCV002815843	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	2021-10-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000726956	SCV003827890	uncertain significance	not provided	2023-11-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149932	SCV003838666	uncertain significance	Cardiomyopathy	2021-11-04	criteria provided, single submitter	clinical testing
KardioGenetik, Herz- und Diabeteszentrum NRW	RCV003327374	SCV004034990	uncertain significance	Dilated cardiomyopathy 1G	2023-06-19	criteria provided, single submitter	clinical testing