Submissions for variant NM_000257.4(MYH7):c.5302G>A (p.Glu1768Lys)

dbSNP: rs397516241

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000467506	SCV000564456	uncertain significance	Hypertrophic cardiomyopathy	2021-03-22	reviewed by expert panel	curation	The c.5302G>A (p.Glu1768Lys) variant in MYH7 has been identified in at least 7 individuals with HCM (PS4_Moderate; Van Driest 2004 PMID:15358028; Bos 2014 PMID:24793961; Murphy 2016 PMID:26914223; Berge 2014 PMID:24111713; Homburger 2016 PMID:27247418; Cecconi 2016 PMID:27600940; LMM SCV000059606.5). In vitro studies showed this variant had a slight effect on protein structure, but no effect on the ability to incorporate into muscle sarcomeres in an experimental system (Wolny 2013 PMID:24047955); however, this evidence is insufficient to apply PS3. Additionally this variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v.2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM2; PP3
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035954	SCV000059606	uncertain significance	not specified	2014-06-05	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Glu1768Lys variant in MYH7 has been reported in 1 individual with HCM (Van Driest 2004) and has also been identified by our laboratory in 1 Caucasian individual with HCM a nd in 1 affected relative with syncope. It was absent from large population stud ies. Glutamic acid (Glu) at position 1768 is highly conserved in mammals and acr oss evolutionarily distant species and the change to lysine (Lys) was predicted to be pathogenic using a computational tool clinically validated by our laborato ry. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role of this variant in disease, the clinical significance is uncertain.
GeneDx	RCV000766469	SCV000208807	uncertain significance	not provided	2015-12-21	criteria provided, single submitter	clinical testing	The E1768K variant in the MYH7 gene has been reported previously in association with HCM and it was not observed in 400 control alleles from individuals of African American and Caucasian ethnic backgrounds (Van Driest et al., 2004). The E1768K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. E1768K results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine residue at a position that is highly conserved throughout evolution. Furthermore, missense variants in nearby residues (A1763T, A1766T, L1769M) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Additionally, E1768K has been observed in multiple unrelated individuals tested for HCM Nevertheless, functional studies show that the E1768K variant had MHC incorporation into myofibrils similar to wild type cells (Wolny et al., 2013). Finally, another clinical laboratory classifies E1768K as a variant of uncertain significance in ClinVar (Landrum et al., 2014).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467506	SCV000546225	pathogenic	Hypertrophic cardiomyopathy	2022-10-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MYH7 function (PMID: 24047955). 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: 43059). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 15358028, 24111713, 24510615, 27247418, 27600940). 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 1768 of the MYH7 protein (p.Glu1768Lys).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000035954	SCV000280362	uncertain significance	not specified	2013-12-09	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu1768Lys, E1768K, (c.5302G>A) in the MYH7 gene. We had initially classified this variant as likely disease causing, however, given the weak case data and the lack of Asian controls, we reclassified it to variant of uncertain significance, probably disease causing in 2014. We now have Asian frequency data from ExAC showing it is rare in that population. Thus we are increasingly feel it is more likely that this variant is in fact disease causing, however it remains classified as a variant of uncertain significance, probably disease. An additional case would probably shift it to likely disease causing. The variant has been seen in at least three patients and possibly as many as five presumably unrelated patients with HCM, not including this patient. Van Driest et al., 2004 reported the variant in a cohort of 350 individuals with HCM, with no specific case data available for this variant, including ancestry data. Bos et al (2014) reported the variant in two patients with HCM in their Mayo cohort who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). Note that these cases may overlap with prior reports by Ackerman's group (ex. van Driest et al 2004) and with the clinical labs since some of these patients likely underwent clinical genetic testing. These two cases also likely overlap with two of the three reported by Kapplinger et al (2014) since that dataset includes Mayo cases and patients referred to Transgenomic for genetic testing. Unfortunately phenotypic data is not provided and so we cannot confirm if cases tested at Transgenomic had HCM. This variant has also been seen in another individual in our center with HCM, also of Asian ancestry. LMM's ClinVar assertion is "uncertain significance", with the following data: "The Glu1768Lys variant in MYH7 has been reported in 1 individual with HCM (Van Driest 2004) and has also been identified by our laboratory in 1 Caucasian individual with HCM and in 1 affected relative with syncope. It was absent from large population studies. Glutamic acid (Glu) at position 1768 is highly conserved in mammals and across evolutionarily distant species and the change to lysine (Lys) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role of this variant in disease, the clinical significance is uncertain." This variant is in the rod portion of MYH7 (exons 24-40) No segregation data is available. This variant changes a polar, acidic glutamic acid to a polar basic lysine. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation taster predicts it to be disease causing. The glutamic acid at codon 1768 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with cardiomyopathy at nearby codons (Leu1769Met, Klassen et al 2008; Ala1766Thr, Girolamni et al 2006). The variant was reported online in 1 of 60,705 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of February 24th, 2015). The phenotype of that individual is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). The variant was not observed in the following laboratory and published control samples: GeneDx reports it was not seen in 304 control individuals, Van Driest et al. reports it was not seen in 400 control alleles.