ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1491G>T (p.Glu497Asp) (rs267606911)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000204929 SCV000059378 likely pathogenic Hypertrophic cardiomyopathy 2017-08-14 criteria provided, single submitter clinical testing The p.Glu497Asp variant in MYH7 has been reported in ?6 individuals with HCM and segregated with disease in 3 affected relatives from 2 families (Arad 2005, Ho 2013, Kapplinger 2014, Homburger 2016, LMM data). This variant has also been rep orted by other clinical laboratories in in ClinVar (Variation ID 14124) and has been identified in 2/9850 Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs267606911). Please note that for diseases with clinical variability or reduced penetrance, pathoge nic variants may be present at a low frequency in the general population. Glutam ic acid (Glu) at position 497 is highly conserved in mammals and across evolutio narily distant species and the change to aspartic acid (Asp) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. T his tool's pathogenic prediction is estimated to be correct 94% of the time (Jor dan 2011). Of note, the p.Glu497Asp variant lies in the head region of the prote in. Missense variants in this region have been reported and statistically indica ted to be more likely to cause disease (Walsh 2016). In summary, although additi onal studies are required to fully establish its clinical significance, the p.Gl u497Asp variant is likely pathogenic. ACMG/AMP Criteria applied (Richards 2015): PS4_Moderate, PP1_Supporting, PP3, PM1.
GeneDx RCV000223873 SCV000208744 likely pathogenic not provided 2016-06-21 criteria provided, single submitter clinical testing The E497D likely pathogenic variant in the MYH7 gene has been reported previously in association with HCM (Aradet al., 2005; Arad et al., 2014; Kapplinger et al., 2014; Lopes et al., 2015). E497D has also been identified inmultiple other individuals referred for HCM genetic testing at GeneDx. So far, segregation data is limited or absent forthese individuals due to the lack of clinical information provided and/or insufficient participation by informativefamily members. Of note, this variant has also been reported in several patients without definitive clinical signs ofcardiomyopathy (Captur et al., 2014; Ho et al., 2015). Nevertheless, E497D was not observed in approximately6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating itis not a common benign variant in these populations.Although the E497D variant is a conservative amino acid substitution, it occurs at a position that is conserved acrossspecies. Functional analysis of the Drosophila myosin heavy chain ortholog and molecular modeling of humanbeta-cardiac myosin suggest that charge reversal of E497 disrupts a salt bridge with R712, which may decreaseATPase activity and actin sliding velocity (Kronert et al., 2015). However, the functional impact of a substitution thatpreserves the negative charge at this residue in the human protein is still unclear.Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional datais required.
Invitae RCV000204929 SCV000261320 pathogenic Hypertrophic cardiomyopathy 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 497 of the MYH7 protein (p.Glu497Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (rs267606911, ExAC no frequency). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 16267253, 23549607, 24510615). ClinVar contains an entry for this variant (Variation ID: 14124). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In addition, experimental studies have shown that residue p.Glu497 of MYH7 is involved in intramolecular interactions and is required for myosin ATPase activity (PMID: 26446785). In summary, this variant is absent from population databases, has been observed in multiple unrelated individuals with hypertrophic cardiomyopathy, and affects a residue important for MYH7 protein function. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000250089 SCV000318467 likely pathogenic Cardiovascular phenotype 2017-05-02 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170512 SCV001333095 likely pathogenic Cardiomyopathy 2018-01-18 criteria provided, single submitter clinical testing
OMIM RCV000015184 SCV000035441 pathogenic Familial hypertrophic cardiomyopathy 1 2005-11-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223873 SCV000280303 likely pathogenic not provided 2014-10-08 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.Glu497Asp (c.1419G>T) in MYH7. The results have been re-reviewed multiple times, most recently on August 27th, 2014. Additional data further supporting pathogenicity was available. Given the strong case data, the segregation data, and the absence in the general population we consider this variant likely disease causing. To the best of our knowledge this variant has been seen in at least 9, but possibly 14 unrelated families with HCM (not including this patient's family). There may be overlap between some of the published cases and cases in our center and in the genetic testing labs databases. We have seen this variant in three families with HCM in our center. The variant was reported in two members of one family with HCM studied by the Seidman group (Arad et al 2005).The proband in this family had apical hypertrophy while the other family member with this variant had massive concentric hypertrophy, syncope, and an ICD, along with comorbid coronary artery disease. For one of the family’s in our center, there is moderate co-segregation data to support the pathogenicity of this variant in that four individuals with HCM either tested positive for this variant or can be inferred to carry it based on pedigree analysis. However, we do not have confirmation of either phenotype or genotype on anyone in this family. The testing was reportedly done as part of a research endeavor. Of note, this case may overlap with the one reported by the Seidman group (Arad et al 2005). We also have segregation data in another family with both the proband and his affected mother having the variant. Per their ClinVar submission(SCV000059378), LMM has seen this variant in 5 probands with HCM. In one of those families another affected individual also had the variant. They classify this as likely pathogenic. Ackerman's group observed the variant in two unrelated patients with HCM in their Mayo cohort who underwent analysis in their local lab (Bos et al 2014). A polar, neutral Glutamate is substituted with a polar, neutral Asparagine therefore this variant change does not affect the net charge. The Glutamate at codon 497 is completely conserved across species as are the neighboring amino acids. In silico analysis with Polyphen-2 predicts this variant to be probably damaging. Per the LMM ClinVar submission, the variant was predicted to be pathogenic using a computational tool, which was validated by our laboratory using a set of cardiomyopathy variants with well-established clinical significance. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Mutation Taster predicts this variant to be disease-causing. Other variants in nearby codons have been reported in association with cardiomyopathy including p.Met493Leu, p.Met493Lys, p.Glu299Lys, p.Glu500Ala, p.Tyr501His, and p.Tyr501Cys. In total the variant has not been seen in ~6,800 published controls and individuals from publicly available population datasets. There is no variation at codon 497 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 10/8/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 10/8/13). The variant was not observed in the following published control samples: Arad et al. did not find this variant in 100 presumed normal control individuals. Unfortunately we don’t have control data from any of the testing laboratories. Bos et al did not observe the variant in 200 ostensibly healthy controls."

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