rs121913617
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_002470.4(MYH3):c.2015G>A(p.Arg672His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R672C) has been classified as Pathogenic.
Frequency
Consequence
NM_002470.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH3 | NM_002470.4 | c.2015G>A | p.Arg672His | missense_variant | 18/41 | ENST00000583535.6 | NP_002461.2 | |
MYH3 | XM_011523870.4 | c.2015G>A | p.Arg672His | missense_variant | 18/41 | XP_011522172.1 | ||
MYH3 | XM_011523871.3 | c.2015G>A | p.Arg672His | missense_variant | 18/41 | XP_011522173.1 | ||
MYH3 | XM_047436127.1 | c.2015G>A | p.Arg672His | missense_variant | 20/43 | XP_047292083.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH3 | ENST00000583535.6 | c.2015G>A | p.Arg672His | missense_variant | 18/41 | 5 | NM_002470.4 | ENSP00000464317 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461374Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 727054
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Freeman-Sheldon syndrome Pathogenic:6
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2006 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | May 17, 2022 | - - |
Likely pathogenic, no assertion criteria provided | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 30, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Nov 07, 2022 | PS4, PM1, PM2, PP3, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Nov 19, 2022 | ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PM6 very strong, PP3 supporting - |
not provided Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 02, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2023 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 25, 2023 | 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). - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Freeman-Sheldon syndrome;C1867440:Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A;C5193098:Arthrogryposis, distal, type 2B3;C5193114:Contractures, pterygia, and variable skeletal fusions syndrome 1B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PS4_Moderate+PP4+PM6+PP3_Moderate+PM5 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at