Submissions for variant NM_145064.3(STAC3):c.851G>C (p.Trp284Ser)

gnomAD frequency: 0.00039  dbSNP: rs140291094

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000074400	SCV000611099	pathogenic	Bailey-Bloch congenital myopathy		criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000074400	SCV000640916	pathogenic	Bailey-Bloch congenital myopathy	2025-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 284 of the STAC3 protein (p.Trp284Ser). This variant is present in population databases (rs140291094, gnomAD 0.1%). This missense change has been observed in individual(s) with Native American myopathy, Carey–Fineman–Ziter syndrome and Moebius syndrome (PMID: 23736855, 28777491). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 88744). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt STAC3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects STAC3 function (PMID: 23736855). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000074400	SCV000893310	pathogenic	Bailey-Bloch congenital myopathy	2018-10-31	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000074400	SCV000924464	pathogenic	Bailey-Bloch congenital myopathy	2018-06-15	criteria provided, single submitter	research	The homozygous p.Trp284Ser variant was identified by our study in one individual with Native American myopathy. This variant is pathogenic based on multiple reports in ClinVar and the literature.
CeGaT Center for Human Genetics Tuebingen	RCV001093315	SCV001250235	pathogenic	not provided	2019-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001093315	SCV001780861	pathogenic	not provided	2022-08-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (reduction of amount, organization, stability, and voltage sensitivity of calcium channels) (Linsley et al., 2017; Horstick et al., 2013); 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: 28003463, 27621462, 28777491, 28676249, 29078335, 23736855, 30168660, 30872186, 34374989, 35205385, 35912995, 35481653, 34208776, 33827624, 33060286)
Revvity Omics, Revvity	RCV000074400	SCV002021965	pathogenic	Bailey-Bloch congenital myopathy	2021-01-13	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000074400	SCV002059117	pathogenic	Bailey-Bloch congenital myopathy	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 28777491, 23736855, PS4_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 28777491, PM3_M) and co-segregated with Myopathy, congenital, Baily-Bloch in multiple affected family members (PMID: 28777491, PP1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.886, 3CNET: 0.861, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000117, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Centogene AG - the Rare Disease Company	RCV000074400	SCV002059800	pathogenic	Bailey-Bloch congenital myopathy	2020-10-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000074400	SCV002571794	pathogenic	Bailey-Bloch congenital myopathy	2022-08-05	criteria provided, single submitter	clinical testing	Variant summary: STAC3 c.851G>C (p.Trp284Ser) results in a non-conservative amino acid change located in the SH3 domain (IPR001452) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 251398 control chromosomes, predominantly at a frequency of 0.0011 within the African or African-American subpopulation in the gnomAD database. c.851G>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Bailey-Bloch Congenital Myopathy and has been found to segregrate with the disease phenotype in multiple families affected with the disorder (e.g. Horstick_2013, Telegrafi_2017, Zaharieva_2018). These data indicate that the variant is very likely to be associated with disease. At least one experimental study examining the effect of the variant protein in a zebrafish model system found that it diminished excitation-contraction coupling in fast twitch muscle, suggesting that the variant affects normal protein function (e.g. Horstick_2013). Ten submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000074400	SCV004024489	pathogenic	Bailey-Bloch congenital myopathy	2023-07-01	criteria provided, single submitter	research
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000074400	SCV004046238	pathogenic	Bailey-Bloch congenital myopathy		criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous and homozygous change in individuals with Bailey-Bloch congenital myopathy (PMID: 30168660, 23736855, 27621462, 28777491, 28003463). Functional studies have shown this variant impairs normal STAC3 protein function (PMID: 23736855). The c.851G>C (p.Trp284Ser) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.00012% (33/282798). It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.851G>C (p.Trp284Ser) variant is classified as Pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000074400	SCV004805058	likely pathogenic	Bailey-Bloch congenital myopathy	2024-03-17	criteria provided, single submitter	research
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000074400	SCV005420383	pathogenic	Bailey-Bloch congenital myopathy	2024-10-04	criteria provided, single submitter	research	PM3,PP1,PM2,PP3
OMIM	RCV000074400	SCV000106010	pathogenic	Bailey-Bloch congenital myopathy	2013-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000074400	SCV000994599	not provided	Bailey-Bloch congenital myopathy		no assertion provided	literature only
Laboratoire Génétique Moléculaire, CHRU TOURS	RCV000074400	SCV002515927	pathogenic	Bailey-Bloch congenital myopathy	2022-05-23	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004757959	SCV005362879	pathogenic	STAC3-related disorder	2024-05-24	no assertion criteria provided	clinical testing	The STAC3 c.851G>C variant is predicted to result in the amino acid substitution p.Trp284Ser. This variant has been reported in the homozygous and compound heterozygous states to be causative for congenital Bailey-Bloch myopathy with susceptibility to malignant hyperthermia (Stamm et al. 2008. PubMed ID: 18553514; Horstick et al. 2013. PubMed ID: 23736855; Telegrafi et al. 2017. PubMed ID: 28777491; Schoonen et al. 2019. PubMed ID: 30872186). This variant is reported in 0.10% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.