rs121913618

Variant names:

• chr17-10641318-G-A
• rs121913618
• NM_002470.4:c.2014C>T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002470.4(MYH3):​c.2014C>T​(p.Arg672Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R672H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH3 NM_002470.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.75

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 19 ACMG points.

• PM1: In a region_of_interest Actin-binding (size 22) in uniprot entity MYH3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_002470.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-10641317-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in the MYH3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 1.7445 (below the threshold of 3.09). Trascript score misZ: 4.649 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.995
• PP5: Variant 17-10641318-G-A is Pathogenic according to our data. Variant chr17-10641318-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10641318-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.2014C>T	p.Arg672Cys	missense_variant	Exon 18 of 41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.2014C>T	p.Arg672Cys	missense_variant	Exon 18 of 41		XP_011522172.1
MYH3	XM_011523871.3	c.2014C>T	p.Arg672Cys	missense_variant	Exon 18 of 41		XP_011522173.1
MYH3	XM_047436127.1	c.2014C>T	p.Arg672Cys	missense_variant	Exon 20 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.2014C>T	p.Arg672Cys	missense_variant	Exon 18 of 41	5	NM_002470.4	ENSP00000464317.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Freeman-Sheldon syndrome Pathogenic:2

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B (CPSFS1B; MIM#618469). While functional studies support a loss of function mechanism for missense variants causing arthrogryposis, distal, type 2A (Freeman-Sheldon) (DA2A; MIM#193700), arthrogryposis, distal, type 2B (Sheldon-Hall) (DA2B; MIM#618436) or contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A (CPSFS1A, MIM#178110), dominant negative has not been excluded as a mechanism (PMID: 26945064). (I) 0108 - This gene is associated with both recessive and dominant disease. Individuals with CPSFS1B have a second hit in the 5' UTR region which affects splicing and is regarded as a hypomorphic allele. Missense variants and inframe variants have been reported for dominant disease (PMID: 29805041, OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Individuals with the same variant present with varying severity (PMID: 29805041). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated myosin head (motor) domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic, and observed in both de novo and familial cases of Freeman-Sheldon syndrome (ClinVar, PMID: 20924721, PMID: 25256237). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Jun 13, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies in Drosophila demonstrate that this variant reduces ATPase activity and causes abnormal muscle structure and function (Rao et al., 2019; Das et al., 2019); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32714615, 28584669, 25740846, 30826400, 26180627, 31966463, 26494722, 25957469, 31085342, 29625835, 31746383, 28205584, 20924721, 30379605, 26275891, 16642020) -

Feb 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 672 of the MYH3 protein (p.Arg672Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant has been reported in several individuals affected with Freeman-Sheldon syndrome, including some in which the variant was found to be de novo (PMID: 16642020, 20924721, 25256237, 25740846). ClinVar contains an entry for this variant (Variation ID: 14139). Experimental studies have shown that this missense change alters MYH3 kinetic properties in skeletal muscle cells (PMID: 25740846, 26945064). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PrimateAI	Pathogenic	0.90	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.98		Loss of MoRF binding (P = 0.0762);
MVP		0.95
MPC		2.2
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.58
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121913618; hg19: chr17-10544635; COSMIC: COSV56869681;