Submissions for variant NM_000257.4(MYH7):c.2785GAG[2] (p.Glu931del)

dbSNP: rs397516172

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000707732	SCV000564439	likely pathogenic	Hypertrophic cardiomyopathy	2021-11-23	reviewed by expert panel	curation	The NM_000257.3(MYH7):c.2791_2793delGAG (p.Glu931del) variant has been reported in at least 8 individuals with HCM (PS4_Moderate; Tesson 1998 PMID:9829907; Richard 2013 PMID:12707239; Walsh 2017 PMID:27532257; Norrish 2019 PMID:31006259; GeneDx pers. comm., Invitae pers. comm., LMM pers. comm., OMGL pers.comm.) and segregated with disease in 5 affected individuals with HCM in 1 family (PP1_Moderate; Tesson 1998 PMID:9829907). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant is a deletion of 1 amino acid at position 931 and is not predicted to alter the protein reading-frame. Given that only 1 amino acid has been deleted, the expert panel felt that adjusting to supporting evidence would be more appropriate in this case (PM4_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_ Moderate; PP1_Moderate; PM2; PM4_Supporting.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000707732	SCV000059478	likely pathogenic	Hypertrophic cardiomyopathy	2014-04-14	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000158830	SCV000208765	likely pathogenic	not provided	2019-10-24	criteria provided, single submitter	clinical testing	In-frame deletion of one amino acid, also referred to as E930del in the published literature due to alternate nomenclature; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as likely pathogenic by the ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel (ClinVar Variant ID 42934 ; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 9829907, 31006259, 12707239, 29300372, 27532257)
Invitae	RCV000707732	SCV000836841	pathogenic	Hypertrophic cardiomyopathy	2023-12-20	criteria provided, single submitter	clinical testing	This variant, c.2791_2793del, results in the deletion of 1 amino acid(s) of the MYH7 protein (p.Glu931del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 9829907, 27532257). It has also been observed to segregate with disease in related individuals. This variant is also known as Glu930 codon deletion. ClinVar contains an entry for this variant (Variation ID: 42934). This variant disrupts the p.Glu931 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15358028, 24111713, 25351510). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.