Submissions for variant NM_000432.4(MYL2):c.274+16_274+17insTC

dbSNP: rs200007468

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625483	SCV000745541	benign	Hypertrophic cardiomyopathy 10	2015-09-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174735	SCV001338024	benign	not specified	2020-01-06	criteria provided, single submitter	clinical testing	Variant summary: MYL2 c.274+16_274+17insCT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 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 0.013 in 251448 control chromosomes in the gnomAD database, including 48 homozygotes. The observed variant frequency is approximately 179.3- fold the estimated maximal allele frequency expected for a pathogenic variant in MYL2 causing Hypertrophic Cardiomyopathy phenotype (7.5e-05), strongly suggesting that the variant is benign. c.274+16_274+17insCT has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy without strong evidence for causality (e.g. Gomez_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001529455	SCV001885629	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001529455	SCV002058033	benign	not provided	2024-11-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000625483	SCV002373613	benign	Hypertrophic cardiomyopathy 10	2025-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000158903	SCV000208838	benign	Cardiomyopathy	2014-09-19	flagged submission	clinical testing	The variant is found in HCM, CARDIOMYOPATHY panel(s).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529455	SCV001742942	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001174735	SCV001923196	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529455	SCV001955339	likely benign	not provided		no assertion criteria provided	clinical testing