Submissions for variant NM_000257.4(MYH7):c.3325A>G (p.Lys1109Glu)

dbSNP: rs1429196201

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000584768	SCV000692504	uncertain significance	Hypertrophic cardiomyopathy 1	2017-03-13	criteria provided, single submitter	research	The MYH7 Lys1109Glu variant has been identified in 1 HCM proband (LMM https://cardiodb.org/ACGV/acgv_variant.php?id=214972). The variant is absent from both the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We identified this variant in an HCM proband (max LVWT= 18mm) of Filipino descent and one other affected family member (max LVWT= 30mm), who was diagnosed after a syncopal event post-exertion, several months later the individual suffered a resuscitated cardiac arrest after which an ICD was implanted. Computational tools SIFT, PolyPhen-2, PolyPhen-HCM and MutationTaster predict this variant to be deleterious. Based on this limited evidence, we classify MYH7 Lys1109Glu as a variant of "uncertain significance".
GeneDx	RCV001755980	SCV002007173	uncertain significance	not provided	2020-10-28	criteria provided, single submitter	clinical testing	Reported in association with cardiomyopathy (Walsh et al., 2017; Burns et al., 2017); however, no specific clinical information was provided; Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 28790153)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000584768	SCV002767990	uncertain significance	Hypertrophic cardiomyopathy 1	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Hypertrophic cardiomyopathy is known to be an incompletely penetrant disease, although data specific to this gene is lacking (PMID: 29300372). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated myosin tail domain (Pfam). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. The variant was reported as pathogenic in an individual with familial HCM (PMID: 28408708) and as a VUS in three further individuals (two related) with HCM (PMID: 27532257, ClinVar). (SP) 0906 - Segregation evidence for this variant is inconclusive, as it has been reported in two family members with HCM with no further details provided (ClinVar). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign