Submissions for variant NM_001267550.2(TTN):c.4289C>A (p.Ala1430Glu)

dbSNP: rs577298130

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001704944	SCV000237994	likely benign	not provided	2019-03-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542098	SCV000643163	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2025-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002327010	SCV002629424	benign	Cardiovascular phenotype	2020-09-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV001704944	SCV003819851	uncertain significance	not provided	2022-06-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150077	SCV003838061	benign	Cardiomyopathy	2022-03-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001704944	SCV005075723	uncertain significance	not provided	2024-06-01	criteria provided, single submitter	clinical testing	TTN: PM2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001704944	SCV005879333	uncertain significance	not provided	2024-08-11	criteria provided, single submitter	clinical testing	The TTN c.4289C>A; p.Ala1430Glu variant is rare in the general population (<0.2% 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 the 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.Ala1430Glu 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001704944	SCV001978469	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001704944	SCV001980522	uncertain significance	not provided		no assertion criteria provided	clinical testing