Submissions for variant NM_000232.5(SGCB):c.341C>T (p.Ser114Phe)

gnomAD frequency: 0.00019  dbSNP: rs150518260

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000271872	SCV000228827	pathogenic	not provided	2018-07-05	criteria provided, single submitter	clinical testing
Athena Diagnostics	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	2022-02-18	criteria provided, single submitter	clinical testing	Published functional studies indicate S114F results in defective intracellular trafficking of sarcoglycan proteins (Sohelli et al., 2012); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23349452, 17994539, 10942431, 20071171, 18996010, 27447704, 26990548, 22095924, 15032976, 10993494, 18285821, 30564623, 30919934, 9032047, 31980526, 31589614, 32528171, 33726816, 8968749)
Illumina Laboratory Services, 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	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 114 of the SGCB protein (p.Ser114Phe). This variant is present in population databases (rs150518260, gnomAD 0.05%). This missense change has been observed in individuals with limb-girdle muscular dystrophy (PMID: 9032047, 10942431, 18285821, 20071171, 23349452, 25135358, 25862795, 26404900). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42035). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SGCB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SGCB function (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 Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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 Genetics, 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 and Genomics, Karolinska University Hospital	RCV000271872	SCV001449905	likely pathogenic	not provided	2017-10-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000177020	SCV002020106	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2E	2023-07-13	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000271872	SCV002501573	pathogenic	not provided	2021-06-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000271872	SCV002563816	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	SGCB: PM3:Very Strong, PM2, PP3, PS3:Supporting
Baylor Genetics	RCV000177020	SCV004208733	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2E	2024-03-25	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