Submissions for variant NM_001267550.2(TTN):c.3133G>A (p.Val1045Met)

gnomAD frequency: 0.00019  dbSNP: rs72647868

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040183	SCV000063874	uncertain significance	not specified	2012-11-07	criteria provided, single submitter	clinical testing	The Val1045Met variant in TTN has not been reported in the literature nor previo usly identified by our laboratory. This variant has been identified in 2/4406 Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs72647868). Computational an alyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, a nd SIFT) suggest that the Val1045Met variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, additional studies are needed to fully assess its clinical significance.
Eurofins Ntd Llc (ga)	RCV000714011	SCV000342089	uncertain significance	not provided	2017-11-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456345	SCV000542883	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-08-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000714011	SCV000714955	likely benign	not provided	2020-09-17	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000714011	SCV000844674	uncertain significance	not provided	2018-05-17	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000714011	SCV000884785	uncertain significance	not provided	2018-02-27	criteria provided, single submitter	clinical testing	The TTN c.3133G>A; p.Val1045Met variant 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. While the clinical significance of such variants is considered uncertain, evidence suggests that vast majority of missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Given the available evidence, the clinical significance of the p.Val1045Met variant cannot be determined with certainty.
Mayo Clinic Laboratories, Mayo Clinic	RCV000714011	SCV002541993	uncertain significance	not provided	2021-07-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433513	SCV002750722	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: seen in unaffected individuals, 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.
Revvity Omics, Revvity	RCV000714011	SCV003823591	uncertain significance	not provided	2023-04-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000714011	SCV005074365	uncertain significance	not provided	2024-06-01	criteria provided, single submitter	clinical testing	TTN: PM2, BP4