VCV000088744.59 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(17)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 88744 Accession: VCV000088744.59

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q13.3 12: 57244322 (GRCh38) [ NCBI UCSC ] 12: 57638105 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 11, 2015	Oct 20, 2024	Mar 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_145064.3:c.851G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_659501.1:p.Trp284Ser	missense
NM_001286256.2:c.734G>C	NP_001273185.1:p.Trp245Ser	missense
NM_001286257.2:c.293G>C	NP_001273186.1:p.Trp98Ser	missense
NM_145064.2:c.763_766delCTCT;615521.0004
NR_104422.2:n.547G>C		non-coding transcript variant
NC_000012.12:g.57244322C>G
NC_000012.11:g.57638105C>G
NG_033835.1:g.11872G>C
	Q96MF2:p.Trp284Ser

... more HGVS ... less HGVS

Protein change

W284S, W245S, W98S

Other names

Canonical SPDI

NC_000012.12:57244321:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Unknown function

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00009

Exome Aggregation Consortium (ExAC) 0.00011

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023

The Genome Aggregation Database (gnomAD) 0.00039

Trans-Omics for Precision Medicine (TOPMed) 0.00045

Links

ClinGen: CA145329 UniProtKB: Q96MF2#VAR_071313 OMIM: 615521.0001 dbSNP: rs140291094 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
STAC3		-	-	GRCh38 GRCh37	259	271

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Bailey-Bloch congenital myopathy	Pathogenic/Likely pathogenic (14)	criteria provided, multiple submitters, no conflicts	Mar 17, 2024	RCV000074400.36
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 22, 2022	RCV001093315.27
STAC3-related disorder	Pathogenic (1)	no assertion criteria provided	May 24, 2024	RCV004757959.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Bailey-Bloch congenital myopathy (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine Study: CMG-BHCMG Accession: SCV000611099.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (1) PubMed: 28777491 Sex: female Geographic origin: Qatar
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bailey-Bloch congenital myopathy Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893310.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Jun 15, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Bailey-Bloch congenital myopathy (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV000924464.1 First in ClinVar: Jun 22, 2019 Last updated: Jun 22, 2019	Comment: 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 … (more) 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. (less)
Pathogenic (Oct 27, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bailey-Bloch congenital myopathy Affected status: yes Allele origin: biparental	Centogene AG - the Rare Disease Company Accession: SCV002059800.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Pathogenic (Aug 05, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Bailey-Bloch congenital myopathy Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002571794.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (3) PubMed: 23736855‚ 28777491‚ 30168660 Comment: 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 … (more) 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. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MYOPATHY, CONGENITAL, BAILEY-BLOCH Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046238.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: 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). … (more) 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. (less)
Pathogenic (Jan 13, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bailey-Bloch congenital myopathy Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002021965.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Nov 19, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Bailey-Bloch congenital myopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000640916.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 28492532‚ 23736855‚ 28777491 Comment: 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 … (more) 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‚ÄìFineman‚ÄìZiter 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. (less)
Likely pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Bailey-Bloch congenital myopathy Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004805058.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bailey-Bloch congenital myopathy Affected status: yes Allele origin: germline	3billion Accession: SCV002059117.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:28777491 PMID:28777491 PMID:23736855 PMID:23736855 Comment: 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 … (more) 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. (less) Clinical Features: Arthrogryposis multiplex congenita (present) , Bilateral talipes equinovarus (present) , Camptodactyly (present) , Cleft palate (present) , Abnormal heart morphology (present) , Distal arthrogryposis (present) … (more) Arthrogryposis multiplex congenita (present) , Bilateral talipes equinovarus (present) , Camptodactyly (present) , Cleft palate (present) , Abnormal heart morphology (present) , Distal arthrogryposis (present) , Downslanted palpebral fissures (present) , Hirsutism (present) , Hypertelorism (present) , Micrognathia (present) , Overlapping fingers (present) , Relative macrocephaly (present) , Short metacarpal (present) , Sudden death (present) , Cryptorchidism (present) (less)
Pathogenic (Aug 22, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001780861.3 First in ClinVar: Aug 13, 2021 Last updated: Mar 04, 2023	Comment: 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., … (more) 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) (less)
Pathogenic (Jul 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Bailey-Bloch congenital myopathy Affected status: yes Allele origin: germline	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand Accession: SCV004024489.2 First in ClinVar: Aug 19, 2023 Last updated: Nov 11, 2023
Pathogenic (Jul 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001250235.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Pathogenic (Jan 01, 2013)	no assertion criteria provided Method: literature only	CONGENITAL MYOPATHY 13 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000106010.5 First in ClinVar: Nov 21, 2013 Last updated: Jul 23, 2024	Publications: PubMed (3) PubMed: 23736855‚ 28777491‚ 30168660 Comment on evidence: In a cohort of 5 families with congenital myopathy-13 (CMYO13; 255995), also known as Native American myopathy and Bailey-Bloch congenital myopathy, Horstick et al. (2013) … (more) In a cohort of 5 families with congenital myopathy-13 (CMYO13; 255995), also known as Native American myopathy and Bailey-Bloch congenital myopathy, Horstick et al. (2013) sequenced the coding regions of the STAC3 gene and identified homozygosity for a c.1046G-C transversion (c.1046G-C, NM_145064) in exon 10, resulting in a trp284-to-ser (W284S; 615521.0001), in all 5 affected individuals. Among 13 unaffected individuals, all obligate carriers were heterozygous for the mutation. The mutation was not found in 3 unaffected, unrelated Lumbee individuals, in 13 Caucasian control individuals, or in the 1000 Genomes Project database. Horstick et al. (2013) created zebrafish with the W284S mutation, which exhibited decreased Ca(2+) transients. Conversely, expression of the normal human STAC3 gene in mutant fish rescued their phenotype. In 2 sibs, born of consanguineous parents from Qatar, with CMYO13, Telegrafi et al. (2017) identified a homozygous W284S mutation, which they referred to as resulting from a c.851G-C transversion (NM_145064.2). These authors noted that the mutation occurs at a highly conserved residue in the first SH3 domain. Two sibs from Puerto Rico with the same phenotype were found to be compound heterozygous for the W284S mutation and a 4-bp deletion (c.763_766delCTCT; 615521.0004), predicted to result in a frameshift and premature termination (Leu255IlefsTer58). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The W284S mutation was filtered against the dbSNP, 1000 Genomes Project, and Exome Variant Server databases; the mutation was found in heterozygous state in 13 of 121,350 alleles in the ExAC database. The 4-bp deletion was not found in the dbSNP database, but was found in heterozygous state in 2 of 121,242 alleles in the ExAC database. Functional studies of the variants and studies of patient cells were not performed, but the report demonstrated that the W284S mutation is not restricted to the Native American population. In 17 patients with CMYO13 from 11 apparently unrelated families of non-Native American descent, Zaharieva et al. (2018) identified homozygosity for the W84S mutation in the STAC3 gene. In another patient (PN5), of Afro-Caribbean descent, they identified compound heterozygosity for the W84S substitution and a splice site mutation (c.997-1G-T; 615521.0005) in STAC3, which abolished the acceptor splice site of exon 12, leading to activation of a cryptic acceptor site within exon 12. cDNA sequencing confirmed a 12-bp in-frame deletion, which eliminated 4 amino acids from the second SH3 domain. The mutations segregated with the disorder in all of the families. (less)
Pathogenic (May 24, 2024)	no assertion criteria provided Method: clinical testing	STAC3-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005362879.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
Pathogenic (May 23, 2022)	no assertion criteria provided Method: clinical testing	Bailey-Bloch congenital myopathy (Autosomal recessive inheritance) Affected status: yes Allele origin: biparental	Laboratoire Génétique Moléculaire, CHRU TOURS Accession: SCV002515927.1 First in ClinVar: May 24, 2022 Last updated: May 24, 2022	Number of individuals with the variant: 7 Age: 1-19 years Sex: mixed Ethnicity/Population group: Comoros Geographic origin: Anjouan Island Testing laboratory: Genetic Lab Reunion Island Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: literature only	Bailey-Bloch congenital myopathy Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000994599.2 First in ClinVar: Oct 01, 2019 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 31219695‚ 23736855 BookShelf: NBK542808 BookShelf: NBK542808
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Comment:

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.

Comment:

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.

Comment:

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‚ÄìFineman‚ÄìZiter 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.

Comment:

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.

Comment:

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)

Comment:

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.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Unknown function			Laboratoire Génétique Moléculaire, CHRU TOURS Accession: SCV002515927.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility.	Zaharieva IT	Human mutation	2018	PMID: 30168660
Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome.	Telegrafi A	American journal of medical genetics. Part A	2017	PMID: 28777491
Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy.	Horstick EJ	Nature communications	2013	PMID: 23736855

Text-mined citations for rs140291094 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs140291094 ...