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

gnomAD frequency: 0.00004  dbSNP: rs886042503

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000498910	SCV000334560	pathogenic	not provided	2018-07-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000498910	SCV000589651	pathogenic	not provided	2017-06-16	criteria provided, single submitter	clinical testing	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."
Illumina Laboratory Services, Illumina	RCV000778734	SCV000915092	likely pathogenic	Qualitative or quantitative defects of beta-sarcoglycan	2017-07-10	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812020	SCV000952318	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2E	2023-12-30	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000812020	SCV001162968	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2E		criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000498910	SCV001449906	pathogenic	not provided	2017-10-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000812020	SCV003825623	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2E	2022-04-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000812020	SCV005665321	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2E	2024-06-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000812020	SCV002083004	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2E	2020-10-16	no assertion criteria provided	clinical testing