Submissions for variant NM_000232.5(SGCB):c.31C>G (p.Gln11Glu)

gnomAD frequency: 0.00023  dbSNP: rs752492870

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000399677	SCV000333606	uncertain significance	not provided	2017-06-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000261367	SCV000449675	uncertain significance	Qualitative or quantitative defects of beta-sarcoglycan	2016-07-19	criteria provided, single submitter	clinical testing	The SGCB c.31C>G (p.Gln11Glu) variant has been reported in one study and was found in a homozygous state in a 14-year-old male with Duchenne muscular dystrophy-like features who lost the ability to walk at the age of 11 (Duggan et al. 1997). The variant was not detected among 100 normal chromosomes. It is reported at a frequency of 0.00095 in the South Asian population of the Exome Aggregation Consortium, but this is based on one allele only and in region of poor coverage. Functional studies conducted in HER-911 cells showed that the variant disrupted membrane localization of the protein, although the mislocalization was rescued by kifunesine treatment (Soheili et al. 2012). Based on the evidence, the p.Gln11Glu variant is classified as a variant of unknown significance but suspicious for pathogenicity 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	RCV000543057	SCV000642378	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2E	2024-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 11 of the SGCB protein (p.Gln11Glu). This variant is present in population databases (rs752492870, gnomAD 0.1%). This missense change has been observed in individual(s) with sarcoglycan deficiency (PMID: 9032047). ClinVar contains an entry for this variant (Variation ID: 282248). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects SGCB function (PMID: 22095924). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000399677	SCV002004040	uncertain significance	not provided	2021-10-08	criteria provided, single submitter	clinical testing	Functional analysis of transfected cells showed that Q11E disrupted localization of the SGCB protein to the cell membrane (Soheili et al., 2012); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9032047, 30564623, 22095924)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002229741	SCV002511432	uncertain significance	not specified	2022-04-24	criteria provided, single submitter	clinical testing	Variant summary: SGCB c.31C>G (p.Gln11Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00023 in 38616 control chromosomes. c.31C>G has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Duggan_1997, Soheilli_2012). These data indicate that the variant is likely to be associated with disease. To our knowledge, no quantitative experimental evidence demonstrating an impact on protein function has been reported, although it has been demonstrated to impair membrane localization of Sarcoglycans in vitro (Soheilli_2012). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000543057	SCV002601586	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2E	2022-10-21	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 1 of the SGCB gene that results in the amino acid substitution of Glutamic Acid for Glutamine at codon 11 (p.Gln11Glu) was detected. This variant c.31C>G (p.Gln11Glu) has not been reported in the 1000 genomes databases. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000543057	SCV002778014	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2E	2021-10-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000543057	SCV003827602	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2E	2023-10-10	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000543057	SCV005061152	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2E		criteria provided, single submitter	clinical testing	The missense c.31C>G(p.Gln11Glu) variant lying in splice region of SGCB gene has been reported previously in individuals affected with muscular dystrophies and myopathies (Soheili T, et al., 2012; Duggan DJ, et al., 1997). Functional studies show that this variant disrupted membrane localization of the protein and affects SGCB function (Soheili T, et al., 2012). The p.Gln11Glu variant has been reported with allele frequency of 0.02% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance (multiple submissions). The amino acid change p.Gln11Glu in SGCB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gln at position 11 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic.
Natera, Inc.	RCV000543057	SCV002082997	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2E	2020-03-21	no assertion criteria provided	clinical testing