Submissions for variant NM_002470.4(MYH3):c.533C>T (p.Thr178Ile)

dbSNP: rs121913619

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
SIB Swiss Institute of Bioinformatics	RCV000015202	SCV000998854	pathogenic	Freeman-Sheldon syndrome	2019-08-21	criteria provided, single submitter	curation	This variant is interpreted as a Pathogenic for Arthrogryposis, distal, type 2A (Freeman-Sheldon), autosomal dominant. The following ACMG Tag(s) were applied: PP3, PM2, PS4-Supporting, PM1, PS3, PM6-Strong.
SIB Swiss Institute of Bioinformatics	RCV000778060	SCV000998855	pathogenic	Arthrogryposis, distal, type 2B3	2019-08-21	criteria provided, single submitter	curation	This variant is interpreted as a Pathogenic for Arthrogryposis, distal, type 2B3 (Sheldon-Hall), autosomal dominant. The following ACMG Tag(s) were applied: PP3, PM2, PS4-Supporting, PM1, PS3, PM6-Strong.
DASA	RCV001849265	SCV002107100	pathogenic	MYH3-related disorder	2022-03-05	criteria provided, single submitter	clinical testing	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 30826400) - PS3_moderate.The c.533C>T;p.(Thr178Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 14140; PMID: 25256237; PMID: 30826400; PMID: 18695058) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Myosin_head) - PM1. This variant is not present in population databases (rs121913619- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 18695058) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001529266	SCV004296742	pathogenic	not provided	2023-04-10	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with autosomal dominant arthrogryposis multiplex congenita (PMID: 16642020, 34136434). 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 threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 178 of the MYH3 protein (p.Thr178Ile). This variant is also known as 602C->T. For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 14140).
3billion	RCV000778060	SCV005905464	pathogenic	Arthrogryposis, distal, type 2B3	2024-03-07	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.94 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.54 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014140 /PMID: 16642020). The variant has been previously reported as de novo in a similarly affected individual (PMID: 34136434). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV000015202	SCV000035459	pathogenic	Freeman-Sheldon syndrome	2008-08-01	no assertion criteria provided	literature only
OMIM	RCV000778060	SCV000914179	pathogenic	Arthrogryposis, distal, type 2B3	2008-08-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529266	SCV001742420	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529266	SCV001959559	pathogenic	not provided		no assertion criteria provided	clinical testing