ClinVar Miner

Submissions for variant NM_000232.5(SGCB):c.341C>T (rs150518260)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000271872 SCV000228827 pathogenic not provided 2018-07-05 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000177020 SCV000255839 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2E 2015-03-05 criteria provided, single submitter clinical testing
GeneDx RCV000271872 SCV000329935 pathogenic not provided 2018-10-30 criteria provided, single submitter clinical testing The S114F pathogenic variant in the SGCB gene has been previously reported multiple times in both homozygous and compound heterozygous patients with LGMD2E (Duggan et al., 1997; Ginjaar et al., 2000; Trabelsi et al., 2008). Functional studies indicate S114F results in defective intracellular trafficking of sarcoglycan proteins (Sohelli et al., 2012). The S114F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals.
Illumina Clinical Services Laboratory,Illumina RCV000340831 SCV000449671 pathogenic Qualitative or quantitative defects of beta-sarcoglycan 2016-09-25 criteria provided, single submitter clinical testing The SGCB c.341C>T (p.Ser114Phe) missense variant has been reported in at least five studies in which it has been identified in a homozygous state in eight individuals with sarcoglycanopathy, in a compound heterozygous state in three affected individuals, and in a heterozygous state in two affected individuals in whom a second variant was not identified (Duggan et al. 1997; Crosbie et al. 2000; Trabelsi et al. 2008; Klinge et al. 2008; Wong-Kisiel et al. 2010). The p.Ser114Phe variant was absent from 50 controls and is reported at a frequency of 0.00047 in the European-American population of the Exome Sequencing Project. Transfection of the p.Ser114Phe variant into HER-911 cells demonstrated accumulation of the protein in the endoplasmic reticulum, indicating the variant disrupts transport of the protein to the cell surface (Soheili et al. 2011). Based on the evidence, the p.Ser114Phe variant is classified as pathogenic for beta-sarcoglycanopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000177020 SCV000642379 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2E 2020-11-01 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 114 of the SGCB protein (p.Ser114Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs150518260, ExAC 0.05%). This variant has been reported in the homozygous or compound heterozygous state in many individuals affected with limb-girdle muscular dystrophy (PMID: 9032047, 25135358, 18285821, 10942431, 25862795, 26404900, 23349452, 20071171). ClinVar contains an entry for this variant (Variation ID: 42035). Experimental studies have shown that this missense change disrupts intracellular transport of sarcoglycan proteins in vitro (PMID: 22095924). For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics RCV000177020 SCV000803527 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2E 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Muscular dystrophy, limb-girdle, type 2E, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2-Supporting => PM2 downgraded in strength to Supporting. PS4-Supporting => Recurrent mutation observed in multiple unrelated patients. (PMID:9032047,20071171,18285821,25135358,25862795). PS3 => Well-established functional studies show a deleterious effect (PMID:22095924).
Broad Institute Rare Disease Group, Broad Institute RCV000177020 SCV001164541 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2E 2018-12-03 criteria provided, single submitter research The homozygous p.Ser114Phe variant in SGCB was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.02706% (75/277202) of chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150518260). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The p.Ser114Phe variant in SGCB has been reported in more than 62 individuals with Limb-Girdle Muscular Dystrophy in the homozygous and heterozygous state (PMID: 22095924, 25862795, 25135358). The presence of this variant in combination with many other possibly pathogenic variants and in individuals with LGMD increases the likelihood that the p.Ser114Phe variant is pathogenic. In vitro functional studies provide some evidence that the p.Ser114Phe variant may impact protein function by impairing membrane localization (PMID: 22095924). This variant has also been reported pathogenic in ClinVar by multiple submitters (Variation ID: 42035). In summary, the clinical significance of the p.Ser114Phe variant is pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PS3, PM3_Strong (Richards 2015).
Myriad Women's Health, Inc. RCV000177020 SCV001193983 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2E 2019-11-11 criteria provided, single submitter clinical testing NM_000232.4(SGCB):c.341C>T(S114F) is classified as pathogenic in the context of beta-sarcoglycanopathy. Sources cited for classification include the following: PMID 22095924, 10993494, 10942431, 18285821, 9032047, and 18996010. Classification of NM_000232.4(SGCB):c.341C>T(S114F) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Ambry Genetics RCV001267013 SCV001445194 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000271872 SCV001446819 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000271872 SCV001449905 likely pathogenic not provided 2017-10-26 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000177020 SCV001132529 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2E 2014-10-29 no assertion criteria provided curation
Natera, Inc. RCV000177020 SCV001460963 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2E 2020-09-16 no assertion criteria provided clinical testing

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