Submissions for variant NM_002470.4(MYH3):c.-9+1G>A

gnomAD frequency: 0.00117  dbSNP: rs557849165

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Genetics Group, University of Otago	RCV000714988	SCV000845789	pathogenic	Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A; Spondylocarpotarsal synostosis syndrome	2018-04-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862011	SCV002205690	pathogenic	not provided	2025-01-29	criteria provided, single submitter	clinical testing	This variant occurs in a non-coding region of the MYH3 gene. It does not change the encoded amino acid sequence of the MYH3 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs557849165, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with clinical features of autosomal recessive MYH3-related conditions (PMID: 29805041, 32902138; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 587706). Studies have shown that this variant alters MYH3 gene expression (PMID: 29805041). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 2, but is expected to preserve the integrity of the reading-frame (PMID: 29805041). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509523	SCV002819768	likely pathogenic	MYH3-related disorder	2022-12-23	criteria provided, single submitter	clinical testing	Variant summary: MYH3 c.-9+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 prime splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and results in loss of part of 5'-UTR sequence (Cameron-Christie_2018). The variant allele was found at a frequency of 0.0027 in 31404 control chromosomes. c.-9+1G>A has been reported in the literature and found in our internal database in individuals affected with MYH3-Related Disorders in compound heterozygous or heterozygous status. These reports do not provide unequivocal conclusions about association of the variant with MYH3-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function. This variant leads to a translational efficiency of 54% relative to that of the wild-type (Cameron-Christie_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic n=3, VUS n=1, Benign n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV001862011	SCV003837177	pathogenic	not provided	2025-02-24	criteria provided, single submitter	clinical testing	RNA studies demonstrate a damaging effect resulting in reduction of translational efficiency (PMID: 29805041); Reported with a second MYH3 variant in patients with complex skeletal anomalies (PMID: 35169139, 37273706); This variant is associated with the following publications: (PMID: 32902138, 34440395, 33726816, Sergi2022[casereport], 34204301, 38444278, 29805041, 37273706, 35169139)
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000785651	SCV004014051	likely pathogenic	Contractures, pterygia, and variable skeletal fusions syndrome 1B		criteria provided, single submitter	clinical testing	This variant affects the canonical donor splice site at the untranslated boundary between exon 2 and intron 2, leading to reduced translational efficiency (Zhao et a., 2022).
Illumina Laboratory Services, Illumina	RCV002509523	SCV004101305	likely pathogenic	MYH3-related disorder	2023-08-08	criteria provided, single submitter	clinical testing	The MYH3 c.-9+1G>A variant results in a substitution at a consensus splice donor site that has been shown to result in abnormal splicing with an increase in transcripts lacking exon 2 (PMID: 29805041). This variant was identified in a compound heterozygous state in at least 9 individuals with spondylocarpotarsal synostosis, multiple pterygium syndrome (MPS), and vertebral fusions, arthrogryposis and multiple pterygia (PMID: 29805041; 34440395; 35169139). The highest frequency of this allele in the Genome Aggregation Database is 0.010640 in the European (Finnish) population, however, this variant is not found in the homozygous state but is flagged as low confidence (version 2.1.1). Functional studies conducted in human cell lines demonstrated that transcripts containing the c.-9+1G>A variant lacking exon 2 display a reduced translational efficiency of 54% compared to wild-type (PMID: 29805041). Based on the available evidence, the c.-9+1G>A variant is classified as likely pathogenic for MYH3-related disorders.
CeGaT Center for Human Genetics Tuebingen	RCV001862011	SCV004142018	likely pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	MYH3: PM3:Strong, PM2:Supporting, PS3:Supporting
Revvity Omics, Revvity	RCV001862011	SCV004236990	pathogenic	not provided	2023-09-15	criteria provided, single submitter	clinical testing
OMIM	RCV000785651	SCV000924286	pathogenic	Contractures, pterygia, and variable skeletal fusions syndrome 1B	2020-02-27	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000991182	SCV001142469	pathogenic	Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A	2020-01-06	no assertion criteria provided	curation	NG_011537.1(NM_002470.3):c.-9+1G>A in the MYH3 gene has an allele frequency of 0.011 in European(Finnish) subpopulation in the gnomAD database. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was detected in multiple individuals with autosomal recessive Spondylocarpotarsal Synostosis Syndrome, compound heterozygous with c.4647+1G>A, c.141T>G, deletion of intron 12 and exon 25 (PMID: 29805041).Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PM3_Strong.
PreventionGenetics, part of Exact Sciences	RCV002509523	SCV004711782	likely pathogenic	MYH3-related disorder	2024-01-08	no assertion criteria provided	clinical testing	The MYH3 c.-9+1G>A variant is located in the 5' untranslated region. This variant has been reported in the compound heterozygous state in at least six individuals from three different families with autosomal recessive spondylocarpotarsal synostosis syndrome (Cameron-Christie et al 2018. PubMed ID: 29805041). This variant was also detected in the compound heterozygous state in patients with MYH3-associated conditions (Hakonen et al. 2020. PubMed ID: 32902138; Dahan-Oliel et al. 2021. PubMed ID: 34440395; Zhao et al. 2022. PubMed ID: 35169139). In addition, functional evidence supports that this variant results in aberrant splicing and reduced translational efficiency (Cameron-Christie et al 2018. PubMed ID: 29805041). Although this variant has an allele frequency up to 1.1% in Finnish Europeans, this variant is suggested to be a hypomorphic allele. In summary, this variant is interpreted as likely pathogenic.