rs121913617

Positions:

• chr17-10641317-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_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:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH3 NM_002470.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 6.17

Genes affected

MYH3 (HGNC:7573): (myosin heavy chain 3) Myosin is a major contractile protein which converts chemical energy into mechanical energy through the hydrolysis of ATP. Myosin is a hexameric protein composed of a pair of myosin heavy chains (MYH) and two pairs of nonidentical light chains. This gene is a member of the MYH family and encodes a protein with an IQ domain and a myosin head-like domain. Mutations in this gene have been associated with two congenital contracture (arthrogryposis) syndromes, Freeman-Sheldon syndrome and Sheldon-Hall syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-10641318-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH3. . Gene score misZ 1.7445 (greater than the threshold 3.09). Trascript score misZ 4.649 (greater than threshold 3.09). GenCC has associacion of gene with spondylocarpotarsal synostosis syndrome, contractures, pterygia, and variable skeletal fusions syndrome 1B, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, digitotalar dysmorphism, autosomal recessive multiple pterygium syndrome, Freeman-Sheldon syndrome, distal arthrogryposis type 2B1, Sheldon-hall syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 17-10641317-C-T is Pathogenic according to our data. Variant chr17-10641317-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10641317-C-T is described in Lovd as [Pathogenic]. Variant chr17-10641317-C-T is described in Lovd as [Pathogenic]. Variant chr17-10641317-C-T is described in Lovd as [Likely_pathogenic].

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	ENSP00000464317.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461374 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Freeman-Sheldon syndrome Pathogenic:6

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, no assertion criteria provided	literature only	OMIM	May 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 30, 2022	- -
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 -
Likely pathogenic, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 17, 2022	- -

not provided Pathogenic:6

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	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	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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, 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. -

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

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PM2_Supporting+PS4_Moderate+PP4+PM6+PP3_Moderate+PM5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Pathogenic	0.87	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.98		Loss of MoRF binding (P = 0.089);
MVP		0.92
MPC		2.1
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.82
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121913617; hg19: chr17-10544634; COSMIC: COSV56863939;