ClinVar Genomic variation as it relates to human health

The p.Glu525Lys variant in MYH7 has been reported as a de novo variant in at least 3 individuals with dilated cardiomyopathy (Lakdawala 2012 PMID: 22464770, LMM data, Invitae data, pers comm.). It was absent from large population studies. Of note, this variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2016 PMID: 19864899). This variant has also been reported in ClinVar (Variation ID 132925). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant cardiomyopathy. ACMG/AMP Criteria applied: PS2_VeryStrong, PM1, PM2_Supporting, PS4_Supporting.

- Variant is absent from gnomAD (both v2 and v3). - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is found within the head region, which is enriched with pathogenic missense variants (PMID: 29300372). - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as likely pathogenic and pathogenic, and observed in individuals with dilated cardiomyopathy. In several individuals, the variant had been shown to be de novo (ClinVar, PMID: 22464770, PMID: 29892087). - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). Additional information: - The mechanism of disease for this gene is not clearly established, however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous, however a recessive inheritance pattern has been observed in severe cases (OMIM). - The condition associated with this gene has incomplete penetrance (PMID: 29300372). - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. - This variant is heterozygous. - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes).

The c.1573G>A, p.Glu525Lys missense variant identified in the MYH7 gene has been reported as de novo in at least two patients with infantile-onset dilated cardiomyopathy [PMID:27532257; PMID: 22464770]. This variant is not reported in gnomAD database indicating this is a rare variant. This variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease [PMID:27532257]. Based on the available evidence, the p.Glu525Lys variant in the MYH7 gene is classified as likely pathogenic.

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 525 of the MYH7 protein (p.Glu525Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 22464770; Invitae). In at least one individual the variant was observed to be de novo. 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. For these reasons, this variant has been classified as Pathogenic.

Reported in a South Indian family with four members diagnosed with HCM between 3-18 years of age and all four affected individuals were heterozygous for this variant and the S215L variant in the TPM1 gene, and homozygous for the D896N variant in the MYH7 gene (PMID: 25607779); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 24503780, 29300372, 22464770, 34935411, 33500567, 25607779)

Converted during submission to Pathogenic.

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.