Submissions for variant NM_001267550.2(TTN):c.22090C>T (p.Arg7364Trp)

gnomAD frequency: 0.00011  dbSNP: rs397517500

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039966	SCV000063657	uncertain significance	not specified	2012-03-22	criteria provided, single submitter	clinical testing	The Arg6120Trp variant (TTN) has not been reported in the literature nor previou sly identified by our laboratory. Arginine at position 6120 is highly conserved across evolutionarily distant species and computational analyses (biochemical a mino acid properties, PolyPhen2, and SIFT) suggest that the Arg6120Trp variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. In summary, additional data is needed to fully assess the cl inical significance of the Arg6120Trp variant.
GeneDx	RCV000039966	SCV000238310	uncertain significance	not specified	2014-02-21	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-CRDM panel(s).
Invitae	RCV000643520	SCV000765207	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001573334	SCV002049469	uncertain significance	not provided	2021-03-10	criteria provided, single submitter	clinical testing	The TTN c.22090C>T; p.Arg7364Trp variant (rs397517500; ClinVar Variation ID: 46696) 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.Arg7364Trp 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.
CeGaT Center for Human Genetics Tuebingen	RCV001573334	SCV002585843	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477118	SCV002797626	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	2021-08-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001573334	SCV003823576	uncertain significance	not provided	2021-03-31	criteria provided, single submitter	clinical testing
Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University	RCV003319175	SCV003932391	uncertain significance	Primary dilated cardiomyopathy	2023-06-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486574	SCV004239854	likely benign	Cardiomyopathy	2023-06-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039966	SCV004804020	likely benign	not specified	2024-01-30	criteria provided, single submitter	clinical testing	Variant summary: TTN c.18358C>T (p.Arg6120Trp) results in a non-conservative amino acid change located in the I-band region of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 248334 control chromosomes, predominantly at a frequency of 0.00059 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.18358C>T has been reported in the literature in individuals affected with Dilated Cardiomyopathy and non-phenotypic individuals receiving DCM/Arthrogryposis multiplex congenita panel testings (examples, Burstein_2021, Laquerriere_2022, Pugh_2014), without strong evidence for causality. These report(s) 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. The following publications have been ascertained in the context of this evaluation (PMID: 32746448, 33820833, 24503780). ClinVar contains an entry for this variant (Variation ID: 46696). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573334	SCV001799047	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001573334	SCV001920801	uncertain significance	not provided		no assertion criteria provided	clinical testing