Submissions for variant NM_001267550.2(TTN):c.105083C>T (p.Thr35028Met)

gnomAD frequency: 0.00001  dbSNP: rs56001826

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001852408	SCV002135727	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-07-31	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is located in the M band of TTN (PMID: 25589632). Variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 35028 of the TTN protein (p.Thr35028Met). This variant is present in population databases (rs56001826, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 203090). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown.
Fulgent Genetics, Fulgent Genetics	RCV002492845	SCV002791237	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	2021-08-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398917	SCV004112612	uncertain significance	TTN-related condition	2023-02-08	criteria provided, single submitter	clinical testing	The TTN c.105083C>T variant is predicted to result in the amino acid substitution p.Thr35028Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0056% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179396259-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GeneDx	RCV000185113	SCV000237938	not provided	not provided	2013-09-13	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 panel(s).
Clinical Genetics, Academic Medical Center	RCV000185113	SCV001918024	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000185113	SCV001932082	uncertain significance	not provided		no assertion criteria provided	clinical testing