Submissions for variant NM_001267550.2(TTN):c.96140C>T (p.Thr32047Met)

gnomAD frequency: 0.00004  dbSNP: rs375640847

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040833	SCV000064524	uncertain significance	not specified	2015-02-20	criteria provided, single submitter	clinical testing	The p.Thr29479Met variant in TTN has been previously identified by our laborator y in 1 Caucasian child with DCM. This variant has also been identified in 4/6672 4 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs375640847). Computational prediction tools and conserv ation analysis do not provide strong support for or against an impact to the pro tein. In summary, the clinical significance of the p.Thr29479Met variant is unce rtain.
GeneDx	RCV000725040	SCV000237819	likely benign	not provided	2018-04-05	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000725040	SCV000333462	uncertain significance	not provided	2015-07-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000643737	SCV000765424	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764305	SCV000895324	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	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725040	SCV001152636	uncertain significance	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000725040	SCV004237077	uncertain significance	not provided	2023-02-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000725040	SCV005875634	uncertain significance	not provided	2024-06-12	criteria provided, single submitter	clinical testing	The TTN c.96140C>T; p.Thr32047Met variant (rs375640847; ClinVar Variation ID: 47564) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database). This variant is reported in the literature in an individual with left ventricular noncompaction (Mazzarotto 2021). 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.Thr32047Met 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). PMID: 26567375. Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. PMID: 22335739. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. PMID: 24625729. Mazzarotto F et al. Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies. Genet Med. 2021 May;23(5):856-864. PMID: 33500567.