Submissions for variant NM_000257.4(MYH7):c.5647G>A (p.Glu1883Lys)

gnomAD frequency: 0.00001  dbSNP: rs121913652

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV001068554	SCV001842671	uncertain significance	Hypertrophic cardiomyopathy	2021-07-26	reviewed by expert panel	curation	NM_000257.4(MYH7):c.5647G>A (p.Glu1883Lys) The c.5647G>A (p.Glu1883Lys) variant in MYH7 has been reported in the homozygous state in 1 individual from a consanguineous family with myosin storage myopathy, HCM and a family history consistent with recessive inheritance (Tajharghi 2007 PMID 17372140) and in 4 individuals with HCM from testing laboratories (PS4_Supporting; Walsh 2017 PMID:27532257; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant has been identified in 0.01% (1/18716) of African/African American chromosomes by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), but absent from all other populations (PM2). In vitro functional studies provide conflicting evidence on the impact of this on protein function, with some suggesting a potential impact (Viswanathan 2017 PMID: 28973424; Armel 2009 PMID: 19336582), while another suggests that it has a similar function as its wild time counterpart (Dahl-Halvarsson PMID 28125727). Therefore, this data is currently insufficient to establish functional impact and apply PS3. 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_Supporting, PM2, PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156689	SCV000206410	uncertain significance	not specified	2014-08-07	criteria provided, single submitter	clinical testing	The Glu1883Lys variant in MYH7 has been reported in homozygosity in 1 individual from a consanguineous mating with myosin storage myopathy, HCM and a family his tory consistent with recessive inheritance (Tajsharghi 2007). However, there is some suspension that this variant does not be the cause of disease in this famil y. First, homozygous mutations in MYH7 would be expected to cause an early onset of disease, which was not observed in that individual. Second, that individual is from an unknown ethnicity and the MYH7 variant maybe a common benign variant in that population. Third, individuals from a consanguineous mating carry many h omozygous variants suggesting that that individual could have other variants tha t are also contributing to disease. This variant was absent from large populatio n studies, though it has been reported in dbSNP without frequency information (d bSNP rs121913652). Glutamic acid (Glu) at position 1883 is highly conserved in m ammals and across evolutionarily distant species and the change to lysine (Lys) was predicted to be pathogenic using a computational tool clinically validated b y our laboratory. This tool's pathogenic prediction is estimated to be correct 9 4% of the time (Jordan 2011). In summary, the clinical significance of the Glu18 83Lys variant is uncertain.
GeneDx	RCV000766473	SCV000208809	uncertain significance	not provided	2018-11-05	criteria provided, single submitter	clinical testing	This variant is denoted Glu1883Lys (aka E1883K) at the protein level and c.5647 G>A at the cDNA level. Tajsharghi et al. (2007) reported the homozygous Glu1883Lys variant in a 44 year old man with myopathy and biventricular hypertrophic cardiomyopathy, among other features. This individual had two affected siblings who presented with myopathy and both died of cardiac failure prior to genetic testing. The parents were consanguinous and unaffected, although presumed heterozygous carriers of Glu1883Lys. The Glu1883Lys mutation is located in the distal end of the filament forming rod region of the MYH7 protein, which is essential for filament assembly. Other mutations in the same domain (Arg1845Trp, Glu1886Lys) have been reported in association with skeletal myopathy and hypertrophic cardiomyopathy, respectively (Tajsharghi et al 2003; Armel et al. 2009), supporting the functional importance of this region of the protein. Furthermore, Glu1883Lys was not observed in up to 400 chromosomes of Caucasian and African American ethnic backgrounds tested at GeneDx, indicating it is not a common benign polymorphism in these populations. The Glu1883Lys variant also has been observed in other unrelated individuals tested for HCM at GeneDx. In summary, with the clinical and molecular information available at this time, we can not conclude unequivocally that the Glu1883Lys variant is a disease-causing mutation or rare benign variant. The variant is found in HCM panel(s).
Invitae	RCV001068554	SCV001233672	uncertain significance	Hypertrophic cardiomyopathy	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1883 of the MYH7 protein (p.Glu1883Lys). This variant is present in population databases (rs121913652, gnomAD 0.01%). This missense change has been observed in individual(s) with myosin storage myopathy and hypertrophic cardiomyopathy (PMID: 17372140, 27532257). ClinVar contains an entry for this variant (Variation ID: 14121). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MYH7 function (PMID: 28125727, 28973424). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002482868	SCV002793389	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-10-15	criteria provided, single submitter	clinical testing
OMIM	RCV000015178	SCV000035435	pathogenic	Myopathy, myosin storage, autosomal recessive	2013-01-01	no assertion criteria provided	literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000156689	SCV000280370	uncertain significance	not specified	2013-06-13	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.Glu1883Lys (c.5647G>A). To the best of our knowledge there are no reports of individuals heterozygous for the variant that carry an HCM diagnosis (as of May 27th, 2015). This variant has been reported in an individual with a myosin storage myopathy and cardiomyopathy (Tajsharghi et al 2007). His parents were second cousins and thus autosomal recessive inheritance was assumed. The patient was found to be homozygous for the variant. He presented at age 44 with symptoms consistent with myosin storage myopathy, biventricular hypertrophy and heart failure. The patient had 2 affected siblings who were not genotyped. They died at ages 57 and 32. Both siblings had skeletal myopathy and died due to heart failure. The parents (presumed heterozygotes) and one other sibling (not genotyped) were reportedly normal though it is unclear if they ever had echocardiograms and the father apparently died of a stroke in his 50s. In their ClinVar entry, LMM notes "some suspension that this variant does not be the cause of disease in this family. First, homozygous mutations in MYH7 would be expected to cause an early onset of disease, which was not observed in that individual. Second, that individual is from an unknown ethnicity and the MYH7 variant maybe a common benign variant in that population. Third, individuals from a consanguineous mating carry many homozygous variants suggesting that that individual could have other variants that are also contributing to disease." The variant is listed in ClinVar with both submitting labs, GeneDx and LMM, classifying it as a variant of uncertain significance (as of May 26th, 2015). Armel et al (2009) studied the functional impact of the variant and found that the variant protein had a reduced ability to assemble properly and the paracrystals formed were degraded by proteolysis more readily (note they refer to the variant as p.Glu1886Lys). Nearly all other cases of myosin storage myopathy reported to date are autosomal dominant. This is a non conservative amino acid change with a negatively charged Glutamic Acid replaced with a positively charged Lysine. The variant is located in the rod region of the MYH7 gene, which is involved in sarcomere filament assembly. Other variants in the same domain (p.Arg1845Trp, p.Glu1886Lys) have been reported with skeletal myopathy and hypertrophic cardiomyopathy, respectively (Tajsharghi et al 2003; Armel et al 2009). In silico analysis with Polyphen predicts this variant to be probably damaging with a score of 0.998, Mutation Taster predicts this variant to be disease causing. In total the variant has not been seen in ~6,700 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 1883 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 6/20/13). Note that this dataset does not match the patient's ancestry. This variant was not detected in 200 presumably healthy individuals of Caucasian or African American descent who were tested at GeneDx. Tajsharghi et al (2007) did not report control data. There is also no variation at this codon listed in 1000 genomes (as of 6/20/13). This variant is listed in dbSNP (rs121913652) and is classified as an HGMD_mutation coding sequence variant. HGMD references Tajsharghi 2007. It is not present in ExAC, which currently has variant cals on ~60,500 individuals (May 27th, 2015).