Submissions for variant NM_000257.4(MYH7):c.2593A>G (p.Lys865Glu)

dbSNP: rs730880749

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000802005	SCV001842658	likely pathogenic	Hypertrophic cardiomyopathy	2021-03-22	reviewed by expert panel	curation	The c.2593A>G (p.Lys865Glu) variant in MYH7 has been identified in 4 individuals with HCM (PS4_Supporting; Homburger 2016 PMID:27247418; GeneDx pers. comm., Invitae pers. comm.). This variant segregated with HCM in 5 affected relatives from 2 families (PP1_Moderate; GeneDx, pers. comm., Invitae pers. comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. 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_Supporting; PP1_Moderate; PM2; PM1
GeneDx	RCV000158550	SCV000208485	likely pathogenic	not provided	2018-12-18	criteria provided, single submitter	clinical testing	The K865E variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. K865E is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The K865 residue is conserved across mammal species, and in silico analysis predicts K865E is damaging to the protein structure/function. Mutations in the same residue (K865R) and in nearby residues (A862V, S866P, S866Y, A868P) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Additionally, the K865E variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, K865E is a good candidate for a disease-causing mutation. The variant is found in HCM panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000802005	SCV000941811	pathogenic	Hypertrophic cardiomyopathy	2022-10-01	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418; Invitae). It has also been observed to segregate with disease in related individuals. 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: 181195). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 865 of the MYH7 protein (p.Lys865Glu).
Fulgent Genetics, Fulgent Genetics	RCV002484973	SCV002778235	likely pathogenic	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2022-02-17	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223827	SCV000280328	uncertain significance	not specified	2014-04-29	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. MYH7 p.Lys865Glu Given the lack of case data, (reviewed below) we consider this variant a variant of uncertain significance. This variant is novel. It is located in the S2domain in exon 22 of the MYH7 gene. The variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and are more likely to impact secondary structure. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation Taster predicts this variant to be disease-causing. The lysine at codon 865 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (Lys865Arg) and nearby codons (Ala862Val, Ser866Pro, Ser866Tyr, Ala868Pro). The variant at the same codon p.Lys865Arg was reported in one individual with HCM in an Italian cohort of 88 patient with HCM. Sequencing was also performed for MYBPC3 and TNNT2 genes, which was negative for this patient. No additional clinical data or segregation was given (Girolami et al., (2006), J Cardiovasc Med) In total the variant has not been seen in ~6,500 published controls and individuals from publicly available population datasets. There is no variation at codon 865 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 1/10/14). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/10/14).