VCV000282860.21 - ClinVar

NM_000232.5(SGCB):c.1_2del (p.Met1fs)

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.

(8)

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_000232.5(SGCB):c.1_2del (p.Met1fs)

Variation ID: 282860 Accession: VCV000282860.21

Type and length

Deletion, 2 bp

Location

Cytogenetic: 4q12 4: 52038258-52038259 (GRCh38) [ NCBI UCSC ] 4: 52904424-52904425 (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	Aug 20, 2017	Feb 14, 2024	Dec 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000232.5:c.1_2del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000223.1:p.Met1fs	frameshift initiator codon variant
NM_000232.4:c.1_2delAT
NC_000004.12:g.52038258_52038259del
NC_000004.11:g.52904424_52904425del
NG_008891.1:g.5061_5062del
LRG_204:g.5061_5062del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000004.12:52038257:AT:

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

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) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00005

Trans-Omics for Precision Medicine (TOPMed) 0.00006

Links

ClinGen: CA10604324 dbSNP: rs886042503 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.
LOC129992585	-	-	-	GRCh38	-	98
SGCB		-	-	GRCh38 GRCh37	497	608

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.
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 18, 2018	RCV000498910.7
Autosomal recessive limb-girdle muscular dystrophy type 2E	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 30, 2023	RCV000812020.13
Qualitative or quantitative defects of beta-sarcoglycan	Likely pathogenic (1)	criteria provided, single submitter	Jul 10, 2017	RCV000778734.4

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 (Jul 18, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000334560.5 First in ClinVar: Dec 06, 2016 Last updated: Sep 03, 2023	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SGCB Number of individuals with the variant: 2 Sex: mixed
Pathogenic (Jun 16, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000589651.4 First in ClinVar: Aug 20, 2017 Last updated: Sep 03, 2023	Comment: The c.1_2delAT pathogenic variant in the SGCB gene has been reported previously in two unrelated individuals with sacroglycanopathy who also a second pathogenic variant in … (more) The c.1_2delAT pathogenic variant in the SGCB gene has been reported previously in two unrelated individuals with sacroglycanopathy who also a second pathogenic variant in SGCB identified (Klinge et al., 2008). Immunohistochemistry of muscle biopies from both patients showed reduction of beta, gamma, and delta sarcoglycan (Klinge et al., 2008). The variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met." (less)
Likely pathogenic (Jul 10, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Beta-sarcoglycanopathy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000915092.2 First in ClinVar: May 27, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 18996010 Comment: The SGCB c.1_2delAT (p.Met1?) variant has been reported in a single study and was found in a compound heterozygous state with the same missense variant … (more) The SGCB c.1_2delAT (p.Met1?) variant has been reported in a single study and was found in a compound heterozygous state with the same missense variant in two unrelated individuals with a severe phenotype of beta-sarcoglycanopathy (Klinge et al. 2008). Control data are unavailable for this variant, and it is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or Genome Aggregation Database. However, the coverage of this genomic region may not have been adequate to provide an accurate estimate of the true population frequency. The p.Met1? variant interrupts the initiation codon, and although functional studies of the variant have not been conducted, both compound heterozygous patients showed absent or reduced beta-sarcoglycan expression on immunohistochemistry of muscle biopsies. Based on the evidence, the p.Met1? variant is classified as likely pathogenic for beta-sarcoglycanopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2E Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001162968.2 First in ClinVar: Feb 28, 2020 Last updated: Sep 03, 2023
Pathogenic (Oct 26, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449906.2 First in ClinVar: Dec 10, 2020 Last updated: Sep 03, 2023	Number of individuals with the variant: 2
Pathogenic (Apr 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2E Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003825623.3 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Dec 30, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2E Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000952318.7 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 12566530‚ 15938573‚ 18996010‚ 25862795 Comment: This sequence change affects the initiator methionine of the SGCB mRNA. The next in-frame methionine is located at codon 22. The frequency data for this … (more) This sequence change affects the initiator methionine of the SGCB mRNA. The next in-frame methionine is located at codon 22. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of the initiator codon has been observed in individuals with clinical features of SGCB-related conditions (PMID: 12566530, 15938573, 18996010, 25862795). ClinVar contains an entry for this variant (Variation ID: 282860). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 16, 2020)	no assertion criteria provided Method: clinical testing	Limb-girdle muscular dystrophy type 2E Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002083004.2 First in ClinVar: Apr 23, 2022 Last updated: Sep 03, 2023

Comment:

The c.1_2delAT pathogenic variant in the SGCB gene has been reported previously in two unrelated individuals with sacroglycanopathy who also a second pathogenic variant in SGCB identified (Klinge et al., 2008). Immunohistochemistry of muscle biopies from both patients showed reduction of beta, gamma, and delta sarcoglycan (Klinge et al., 2008). The variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met."

Comment:

The SGCB c.1_2delAT (p.Met1?) variant has been reported in a single study and was found in a compound heterozygous state with the same missense variant in two unrelated individuals with a severe phenotype of beta-sarcoglycanopathy (Klinge et al. 2008). Control data are unavailable for this variant, and it is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or Genome Aggregation Database. However, the coverage of this genomic region may not have been adequate to provide an accurate estimate of the true population frequency. The p.Met1? variant interrupts the initiation codon, and although functional studies of the variant have not been conducted, both compound heterozygous patients showed absent or reduced beta-sarcoglycan expression on immunohistochemistry of muscle biopsies. Based on the evidence, the p.Met1? variant is classified as likely pathogenic for beta-sarcoglycanopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

This sequence change affects the initiator methionine of the SGCB mRNA. The next in-frame methionine is located at codon 22. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of the initiator codon has been observed in individuals with clinical features of SGCB-related conditions (PMID: 12566530, 15938573, 18996010, 25862795). ClinVar contains an entry for this variant (Variation ID: 282860). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical and genetic spectrum in limb-girdle muscular dystrophy type 2E.	Semplicini C	Neurology	2015	PMID: 25862795
Sarcoglycanopathies: can muscle immunoanalysis predict the genotype?	Klinge L	Neuromuscular disorders : NMD	2008	PMID: 18996010
Beta-sarcoglycan gene mutations in Turkey.	Balci B	Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology	2004	PMID: 15938573
Genotype-phenotype correlations in 35 Brazilian families with sarcoglycanopathies including the description of three novel mutations.	Moreira ES	Journal of medical genetics	2003	PMID: 12566530
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SGCB	-	-	-	-

Text-mined citations for rs886042503 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000232.5(SGCB):c.1_2del (p.Met1fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886042503 ...