ClinVar Genomic variation as it relates to human health

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PM6 very strong, PP3 supporting

Published functional studies demonstrate a damaging effect resulting in reduced ATPase activity (Das et al., 2019); 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: 30266093, 26996280, 28584669, 26578207, 32392656, 16642020, 30826400, 32732226, 34367232, 34664542, 33820833, 33016623)

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg672 amino acid residue in MYH3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16642020, 20924721, 25256237, 25740846, 26945064). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MYH3 function (PMID: 30826400). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH3 protein function. ClinVar contains an entry for this variant (Variation ID: 14138). This variant is also known as 2084G->A. This missense change has been observed in individual(s) with autosomal dominant distal arthrogryposis type 2A and/or clinical features of MYH3-related conditions (PMID: 16642020, 26996280, 28584669, 32732226). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 672 of the MYH3 protein (p.Arg672His).

PS4, PM1, PM2, PP3, PP5

The MYH3 c.2015G>A; p.Arg672His variant (rs121913617) is reported in the literature as one of the most common variants in individuals affected with Freeman-Sheldon syndrome (FSS), a severe form of distal arthrogryposis (Ali 2017, Bowman 2022, Hague 2016, He 2021, Laquerriere 2022, Toydemir 2006). This variant is also reported in ClinVar (Variation ID: 14138), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.814), and functional analyses of the variant protein show defects in myosin function (Das 2019, Walklate 2016). Additionally, another variant at the same codon (c.2014C>T; p.Arg672Cys) is reported in patients affected with FSS, and is considered pathogenic (Al-Haggar 2011, Toydemir 2006). Based on available information, the p.Arg672His variant is considered to be pathogenic. References: Al-Haggar M et al. p.R672C mutation of MYH3 gene in an Egyptian infant presented with Freeman-Sheldon syndrome. Indian J Pediatr. 2011 Jan;78(1):103-5. PMID: 20924721. Ali AM et al. Freeman-Sheldon Syndrome: First Molecularly Confirmed Case from Sub-Saharan Africa. Case Rep Genet. 2017;2017:9327169. PMID: 28584669. Bowman S et al. A case of blepharophimosis: Freeman Sheldon syndrome. Ophthalmic Genet. 2022 Feb;43(1):130-133. PMID: 34664542. Das S et al. Myosin heavy chain mutations that cause Freeman-Sheldon syndrome lead to muscle structural and functional defects in Drosophila. Dev Biol. 2019 May 15;449(2):90-98. PMID: 30826400. Hague J et al. Molecularly proven mosaicism in phenotypically normal parent of a girl with Freeman-Sheldon Syndrome caused by a pathogenic MYH3 mutation. Am J Med Genet A. 2016 Jun;170(6):1608-12. PMID: 26996280. He M et al. The Added Value of Whole-Exome Sequencing for Anomalous Fetuses With Detailed Prenatal Ultrasound and Postnatal Phenotype. Front Genet. 2021 Jul 22;12:627204. PMID: 34367232. Laquerriere A et al. Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita. J Med Genet. 2022 Jun;59(6):559-567. PMID: 33820833. Toydemir RM et al. Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nat Genet. 2006 May;38(5):561-5. PMID: 16642020. Walklate J et al. The Most Prevalent Freeman-Sheldon Syndrome Mutations in the Embryonic Myosin Motor Share Functional Defects. J Biol Chem. 2016 May 6;291(19):10318-31. PMID: 26945064.