Submissions for variant NM_002471.4(MYH6):c.3979-8_3979-7delinsGC

dbSNP: rs727503235

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151214	SCV000199054	uncertain significance	not specified	2014-06-19	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The 3979-8_3979-7de linsGC in MYH6 has been identified by our laboratory in 2 adults with DCM +/- co nduction system disease. Data from large populations studies is insufficient to assess the frequency of this variant. This region of intron 28 includes a homopo lymer region with a string of C divided by a single T and is highly variable wit h multiple variations on this sequence having been identified. Due the variabili ty that has been seen in this region and because the MYH6 gene has not yet been strongly associated with cardiomyopathy, this variant is less likely to contribu te to disease. In summary, though its clinical significance is uncertain, the va riation in this region suggests that it is more likely to be benign.
Invitae	RCV000228002	SCV000287417	likely benign	Hypertrophic cardiomyopathy 14	2023-11-08	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769402	SCV000900794	uncertain significance	Cardiomyopathy	2015-11-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151214	SCV000919826	benign	not specified	2021-03-15	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.3979-8_3979-7delinsGC 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. This variant is reported as two separate variants in gnomAD, specifically c.3979-8C>G with an allele frequency of 0.001990 in 181896 control chromosomes (including 3 homozygotes) and c.3979-7T>C with an allele frequency of 0.05366 in 162742 control chromosomes (also including 3 homozygotes). Read data in gnomAD show the two variants in cis in multiple individuals (heterozygous and homozygous). Both frequencies significantly exceed the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.3979-8_3979-7delinsGC in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with a pathogenic variant has been reported (MYBPC3 c.2827C>T, p.Arg943X; Internal testing), providing further supporting evidence for a benign role. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance while another ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001636691	SCV001848668	benign	not provided	2016-11-17	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000151214	SCV001954890	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000151214	SCV001973269	benign	not specified		no assertion criteria provided	clinical testing