17-10645725-C-T

Position:

• chr17-10645725-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_002470.4(MYH3):​c.1123G>A​(p.Glu375Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: MYH3 NM_002470.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: 7.91

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.986
• PP5: Variant 17-10645725-C-T is Pathogenic according to our data. Variant chr17-10645725-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14143.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2, Pathogenic=1}. Variant chr17-10645725-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-10645725-C-T is described in Lovd as [Pathogenic]. Variant chr17-10645725-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH3	NM_002470.4	c.1123G>A	p.Glu375Lys	missense_variant	12/41	ENST00000583535.6
MYH3	XM_011523870.4	c.1123G>A	p.Glu375Lys	missense_variant	12/41
MYH3	XM_011523871.3	c.1123G>A	p.Glu375Lys	missense_variant	12/41
MYH3	XM_047436127.1	c.1123G>A	p.Glu375Lys	missense_variant	14/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH3	ENST00000583535.6	c.1123G>A	p.Glu375Lys	missense_variant	12/41	5	NM_002470.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 63

GnomAD4 genome Cov.: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 07, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 14143). This missense change has been observed in individuals with distal arthrogryposis (PMID: 16642020, 26578207, 31030430). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 375 of the MYH3 protein (p.Glu375Lys). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31030430, 19309503, 29625835, 17380469, 16642020, 26578207) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 26, 2021	- -

Arthrogryposis, distal, type 2B3 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Aug 21, 2019	This variant is interpreted as a variant of uncertain significance for Arthrogryposis, distal, 2B3, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PP3, PM1. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2006	- -

MYH3-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 06, 2022

The MYH3 c.1123G>A variant is predicted to result in the amino acid substitution p.Glu375Lys. This variant has been reported in the heterozygous state in at least one family with distal arthrogryposis (reported as 1192G>A, p.Glu375Lys in Toydemir et al. 2006. PubMed ID: 16642020). At PreventionGenetics, we have observed this variant in the heterozygous state in additional individuals with distal arthrogryposis (Internal Data, PreventionGenetics). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic for autosomal dominant distal arthrogryposis. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.90
MutPred		0.86		Gain of ubiquitination at E375 (P = 0.0051);
MVP		0.86
MPC		2.0
ClinPred		0.98	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121913621; hg19: chr17-10549042; COSMIC: COSV56862372; COSMIC: COSV56862372;