ClinVar Miner

Submissions for variant NM_000232.4(SGCB):c.341C>T (p.Ser114Phe) (rs150518260)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000177020 SCV000255839 pathogenic Limb-girdle muscular dystrophy, type 2E 2015-03-05 criteria provided, single submitter clinical testing
Counsyl RCV000177020 SCV000677899 likely pathogenic Limb-girdle muscular dystrophy, type 2E 2015-10-27 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000271872 SCV000228827 pathogenic not provided 2018-07-05 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 Beta-sarcoglycanopathy 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 Limb-girdle muscular dystrophy, type 2E 2019-01-02 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 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).

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