rs150518260

Positions:

• chr4-52029766-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000232.5(SGCB):​c.341C>T​(p.Ser114Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000469 in 1,613,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: SGCB NM_000232.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 9.73

Genes affected

SGCB (HGNC:10806): (sarcoglycan beta) This gene encodes a member of the sarcoglycan family. Sarcoglycans are transmembrane components in the dystrophin-glycoprotein complex which help stabilize the muscle fiber membranes and link the muscle cytoskeleton to the extracellular matrix. Mutations in this gene have been associated with limb-girdle muscular dystrophy.[provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a topological_domain Extracellular (size 231) in uniprot entity SGCB_HUMAN there are 44 pathogenic changes around while only 2 benign (96%) in NM_000232.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851
• PP5: Variant 4-52029766-G-A is Pathogenic according to our data. Variant chr4-52029766-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-52029766-G-A is described in Lovd as [Pathogenic]. Variant chr4-52029766-G-A is described in Lovd as [Pathogenic]. Variant chr4-52029766-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCB	NM_000232.5	c.341C>T	p.Ser114Phe	missense_variant	3/6	ENST00000381431.10	NP_000223.1
SGCB	XM_047416074.1	c.131C>T	p.Ser44Phe	missense_variant	2/5		XP_047272030.1
SGCB	XM_047416075.1	c.44C>T	p.Ser15Phe	missense_variant	2/5		XP_047272031.1
SGCB	XM_047416076.1	c.44C>T	p.Ser15Phe	missense_variant	2/5		XP_047272032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10	c.341C>T	p.Ser114Phe	missense_variant	3/6	1	NM_000232.5	ENSP00000370839.6

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 151976 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000282 AC: 71 AN: 251470 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135904

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000563

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000498 AC: 728 AN: 1461308 Hom.: 0 Cov.: 30 AF XY: 0.000486 AC XY: 353 AN XY: 727024

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.000635

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74346

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000350 Hom.: 1

Bravo AF: 0.000200

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000382

EpiControl AF: 0.000533

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2E Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 11, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 12, 2024	- -
Pathogenic, no assertion criteria provided	curation	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Oct 29, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	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. -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 05, 2015	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	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). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	SGCB: PM3:Very Strong, PM2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 28, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Oct 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 05, 2018	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2014

- -

Qualitative or quantitative defects of beta-sarcoglycan Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 25, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.7	L
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.84
MVP		0.97
MPC		0.35
ClinPred		0.37	T
GERP RS		5.3
Varity_R		0.56
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs150518260; hg19: chr4-52895932;