ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1573G>A (p.Glu525Lys) (rs606231324)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154447 SCV000204116 pathogenic Primary dilated cardiomyopathy; Left ventricular noncompaction 2017-06-02 criteria provided, single submitter clinical testing The p.Glu525Lys variant in MYH7 has been identified as de novo in at least 2 ind ividuals with infantile-onset DCM (Lakdawala 2012, LMM data, pers comm.). It wa s absent from large population studies. This variant has been reported in Clinva r (Variation ID:132925). Of note, this variant lies in the head region of the p rotein. Missense variants in this region have been reported and statistically in dicated to be more likely to cause disease (Walsh 2016). In summary, this varian t meets criteria to be classified as pathogenic for cardiomyopathy in an autosom al dominant manner based upon occurrence as a de novo, absence from controls, an d presence in critical region of the protein.
Invitae RCV000466357 SCV000546236 pathogenic Hypertrophic cardiomyopathy 2016-12-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 525 of the MYH7 protein (p.Glu525Lys). 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 (rs606231324, ExAC no frequency). This variant arose de novo in two unrelated individual affected with dilated cardiomyopathy (PMID: 22464770, Invitae). ClinVar contains an entry for this variant (Variation ID: 132925). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar RCV000578453 SCV000680308 pathogenic Dilated cardiomyopathy 1S 2017-11-08 criteria provided, single submitter clinical testing
Evolutionary and Medical Genetics Laboratory, Centre for Cellular and Molecular Biology RCV000148974 SCV000154223 pathogenic Familial cardiomyopathy no assertion criteria provided not provided Converted during submission to Pathogenic.
Blueprint Genetics RCV000157356 SCV000207094 likely pathogenic Left ventricular noncompaction cardiomyopathy 2014-06-04 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786168 SCV000924862 likely pathogenic not provided 2017-06-21 no assertion criteria provided provider interpretation Found to be de novo in a male infant diagnosed at 2 weeks of age with DCM/LVNC at our center. There is no known family history of DCM/LVNC. Genetic testing was conducted through the Invitae laboratory and included 86 genes associated with heritable cardiomyopathies. The following genes were evaluated for sequence changes and exonic deletions/duplications: ABCC9, ACADVL, ACTC1, ACTN2, AGL, ALMS1, ANKRD1, BAG3, CACNA1C, CALR3, CAV3, CHRM2, CRYAB, CSRP3, CTF1, CTNNA3, DES, DMD, DNAJC19, DOLK, DSC2, DSG2, DSP, DTNA, ELAC2, EMD, EYA4, FHL1, FHL2, FKRP, FKTN, GAA, GATA4, GATA6, GATAD1, GLA, HCN4, ILK, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, LRRC10, MTO1, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOM1, MYOZ2, MYPN, NEBL, NEXN, NKX2-5, NPPA, PDLIM3, PKP2, PLEKHM2, PLN, PRDM16, PRKAG2, RAF1, RBM20, RYR2, SCN5A, SGCD, SLC22A5, TAZ, TCAP, TGFB3, TMEM43, TMEM70, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, TXNRD2, VCL. The following genes were evaluated for sequence changes only: SDHA Both parents subsequently tested negative for the variant at Invitae, with paternity molecularly confirmed. p.Glu525Lys (E525K; c.1573G>A) in exon 15 of the MYH7 gene (NM_000257.3) Chromosome position: 14:23897714 C / T Based on the information reviewed below, we classify it as Likely Pathogenic, concluding that there is sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing in at-risk relatives. p.Glu525Lys has been reported as arising de novo in one individual affected with dilated cardiomyopathy and tested at the Laboratory for Molecular Medicine (PMID: 22464770, Lakdawala et al. 2012). This is a nonconservative amino acid change, resulting in the replacement of a negatively charged Glutamic Acid with a positively charged Lysine. Glutamic Acid at this location is absolutely conserved across ~100 vertebrate species for which we have data, as are the adjacent residues. Invitae reports that algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. An analysis by Homburger et al. (2016), specific to HCM, identifies this residue as being in a portion of the myosin head which is enriched for pathogenic variation in surface residues in the pre-stroke conformation. In total the variant has not been seen in >140,000 individuals from publicly available population datasets. Variation at this codon has not been seen in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian). These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases. There is 50x sequencing coverage for almost all ExAC participants at this site. It is also not seen in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which expands upon ExAC to include variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi Jewish descent.

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