ClinVar Genomic variation as it relates to human health

The E930K pathogenic variant in the MYH7 gene has been previously reported in multiple individuals with HCM (Marian et al., 1995; Woo et al., 2003; Song et al., 2005; Millat et al., 2010; Zou et al., 2013; Walsh et al., 2017). It has also been shown to segregate with HCM in multiple affected relatives from multiple families, as reported by Marian et al. (1995), Song et al. (2005), a different clinical laboratory (ClinVar SCV000059477.4, Landrum et al., 2016), and observed at GeneDx. The E930K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, likely pathogenic missense variants in nearby residues (E927K, D928N, E929K, E935K, E935V), and in the same residue (E930Q), have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014), further supporting the functional importance of this residue and region of the protein. Furthermore, the E930K variant is not observed in large population cohorts (Lek et al., 2016).

The p.E930K pathogenic mutation (also known as c.2788G>A), located in coding exon 21 of the MYH7 gene, results from a G to A substitution at nucleotide position 2788. The glutamic acid at codon 930 is replaced by lysine, an amino acid with similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been identified in one Chinese family with hypertrophic cardiomyopathy (HCM) and sudden cardiac death, segregating with disease in three affected individuals diagnosed with HCM (Song L et al. Clin. Chim. Acta. 2005;351:209-216). This alteration has also been reported in additional probands with HCM (Millat G etal. Eur J Med Genet 2010;53:261-267; Woo A etal. Heart 2003;89:1179-1185; Weissler-Snir A et al. Circ Cardiovasc Imaging, 2017 Feb;10:[ePub ahead of print]). Another alteration at the same codon, p.E930Q (c.2788G>C), has been detected in several individuals with HCM (Girolami F et al. J Cardiovasc Med (Hagerstown), 2006 Aug;7:601-7; Olivotto I et al. Mayo Clin Proc, 2008 Jun;83:630-8; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Ware SM et al. J Am Heart Assoc, 2021 May;10:e017731; Burstein DS et al. Pediatr Res, 2021 May;89:1470-1476; Park J et al. Hum Mol Genet, 2022 Mar;31:827-837). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

MYH7: PM2, PM5, PP1:Moderate, PS4:Moderate, PP2, PP4

For these reasons, this variant has been classified as Pathogenic. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 42933). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 9154300, 12975413, 19134269, 20800588, 27532257). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 930 of the MYH7 protein (p.Glu930Lys).

The Glu930Lys variant in MYH7 has been reported in >10 individuals with HCM from 3 families and segregated with disease in 2 affected family members (Abchee 199 7, Woo 2003, Song 2005, Wang 2008). This variant was also identified by our labo ratory in 3 Caucasian individuals with HCM and segregated with disease in 5 affe cted individuals from 2 different families. Glutamic acid (Glu) at position 930 is highly conserved in mammals and across evolutionarily distant species and the change to Lysine (Lys) was predicted to be pathogenic using a computational too l clinically validated by our laboratory. This tool's pathogenic prediction is e stimated to be correct 94% of the time (Jordan 2011). In summary, this variant m eets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon computational evidence, absence from controls, and segregation studi es.