Submissions for variant NM_001267550.2(TTN):c.98866A>G (p.Met32956Val)

gnomAD frequency: 0.00005  dbSNP: rs727503538

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152169	SCV000200894	uncertain significance	not specified	2014-05-01	criteria provided, single submitter	clinical testing	The Met30388Val variant in TTN has not been previously reported in individuals w ith cardiomyopathy or in large population studies. Computational prediction tool s and conservation analysis do not provide strong support for or against an impa ct to the protein. In summary, the clinical significance of this variant is unce rtain.
Invitae	RCV000462130	SCV000542383	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2016-12-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620518	SCV000735264	likely benign	Cardiovascular phenotype	2020-03-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV000764303	SCV000895322	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
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000152169	SCV001160291	uncertain significance	not specified	2019-03-01	criteria provided, single submitter	clinical testing	The TTN c.91162A>G; p.Met30388Val variant (rs727503538; ClinVar Variation ID: 165678) is rare in the general population (<1% 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.Met30388Val variant cannot be determined with certainty.
Revvity Omics, Revvity	RCV001701771	SCV003822232	uncertain significance	not provided	2021-01-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415992	SCV004116514	uncertain significance	TTN-related condition	2022-10-11	criteria provided, single submitter	clinical testing	The TTN c.98866A>G variant is predicted to result in the amino acid substitution p.Met32956Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179403796-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701771	SCV001930969	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001701771	SCV001962721	uncertain significance	not provided		no assertion criteria provided	clinical testing