Submissions for variant NM_001276345.2(TNNT2):c.412-6_412-4del

dbSNP: rs397516462

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036582	SCV000060237	likely benign	not specified	2010-11-09	criteria provided, single submitter	clinical testing	The 382-6_382-4delCCT variant has not been reported in the literature but has be en detected by our laboratory in two Asian probands, one with HCM and one with D CM. The HCM case already had another variant thought to be causative for disease . In silico tools do not predict an impact to the splicing consensus sequence. I n summary, this data suggests this variant is likely benign.
Invitae	RCV000560677	SCV000646897	likely benign	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771864	SCV000904585	benign	Cardiomyopathy	2018-07-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771864	SCV002042847	benign	Cardiomyopathy	2020-10-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036582	SCV004020748	benign	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: TNNT2 c.382-6_382-4delCCT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 249246 control chromosomes, predominantly at a frequency of 0.0016 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in TNNT2 causing Cardiomyopathy phenotype (0.00018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.382-6_382-4delCCT has been reported in the literature in individuals affected with Cardiomyopathy (Lakdawala_2012 and Pugh_2014) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24503780, 22464770). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV003445104	SCV004173777	benign	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003445105	SCV004173778	benign	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003445103	SCV004173779	benign	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing