rs1555527166

Positions:

• chr17-10648562-GGGA-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_002470.4(MYH3):​c.727_729delTCC​(p.Ser243del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH3 NM_002470.4 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 10.0

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_002470.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-10648562-GGGA-G is Pathogenic according to our data. Variant chr17-10648562-GGGA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10648562-GGGA-G is described in Lovd as [Pathogenic]. Variant chr17-10648562-GGGA-G is described in Lovd as [Likely_pathogenic]. Variant chr17-10648562-GGGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH3	NM_002470.4	c.727_729delTCC	p.Ser243del	conservative_inframe_deletion	8/41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.727_729delTCC	p.Ser243del	conservative_inframe_deletion	8/41		XP_011522172.1
MYH3	XM_011523871.3	c.727_729delTCC	p.Ser243del	conservative_inframe_deletion	8/41		XP_011522173.1
MYH3	XM_047436127.1	c.727_729delTCC	p.Ser243del	conservative_inframe_deletion	10/43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.727_729delTCC	p.Ser243del	conservative_inframe_deletion	8/41	5	NM_002470.4	ENSP00000464317.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A Pathogenic:3

Pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	May 19, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Feb 20, 2024	The MYH3 c.727_729del (p.Ser243del) variant has been reported in at least two unrelated individuals with contractures, pterygia, and spondylocarpotarsal fusion syndrome-1A and is reported to segregate with disease in three individuals in one family (Chong JX et al., PMID: 25957469; Zieba J et al., PMID: 28205585). This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant is predicted to cause a change in the length of the protein due to an in-frame deletion of a serine residue in a non-repeat region. This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by three submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 07, 2015	- -

Spondylocarpotarsal synostosis syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Feb 16, 2017

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 13, 2016

The c.727_729delTCC variant in the MYH3 gene has been reported previously segregating in a family with distal arthrogryposis type 8 (Chong et al., 2015). The c.727_729delTCC variant causes an in-frame deletion of one amnio acid, Serine 243, denoted p.Ser243del. The c.727_729delTCC variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.727_729delTCC as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

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: rs1555527166; hg19: chr17-10551879;