Submissions for variant NM_001267550.2(TTN):c.32093G>A (p.Arg10698Gln)

gnomAD frequency: 0.00039  dbSNP: rs200161147

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223128	SCV000272625	uncertain significance	not specified	2015-05-18	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Arg9454Gln va riant in TTN has not been previously reported in individuals with cardiomyopathy , but has been identified in 0.1% (19/16434) of South Asian chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs20016 1147). Arginine (Arg) at position 9454 is not conserved in mammals or evolutiona rily distant species and 1 mammal (weddell seal) carries a glutamine (Gln) at th is position, raising the possibility that this change may be tolerated. In addit ion, this variant is located in the last three bases of the exon, which is part of the 5? splice region. Computational tools do not suggest an impact to splicin g. However, this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Arg9454Gln variant is unce rtain, it's frequency and the presence of the variant amino acid in another mamm al suggest it is more likely to be benign.
Invitae	RCV001080545	SCV000642980	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-28	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000184445	SCV000701346	uncertain significance	not provided	2018-02-13	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768884	SCV000900257	uncertain significance	Cardiomyopathy	2017-03-21	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000223128	SCV001880240	likely benign	not specified	2021-03-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000184445	SCV004152488	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	TTN: BP4
PreventionGenetics, part of Exact Sciences	RCV003895218	SCV004717208	uncertain significance	TTN-related condition	2023-10-28	criteria provided, single submitter	clinical testing	The TTN c.32093G>A variant is predicted to result in the amino acid substitution p.Arg10698Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.11% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179553782-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GeneDx	RCV000184445	SCV000237077	not provided	not provided	2014-04-14	no assertion provided	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).
Clinical Genetics, Academic Medical Center	RCV000184445	SCV001919831	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000184445	SCV001958092	likely benign	not provided		no assertion criteria provided	clinical testing