ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5647G>A (p.Glu1883Lys) (rs121913652)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1883 of the MYH7 protein (p.Glu1883Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous in an individual with myosin storage myopathy (PMID: 17372140). This variant has also been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 14121). This variant has been reported to have conflicting or insufficient data to determine the effect on MYH7 protein 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.
OMIM RCV000015178 SCV000035435 pathogenic Myopathy, myosin storage, autosomal recessive 2009-04-14 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).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.