rs150518260

Variant names:

• chr4-52029766-G-A
• rs150518260
• NM_000232.5:c.341C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PP2 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 O:1
• Conservation: PhyloP100: 9.73
• Publications: 22 publications found

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]

SGCB Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2E

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000232.5
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.0049736 (below the threshold of 3.09). Trascript score misZ: -0.4279 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive limb-girdle muscular dystrophy type 2E, autosomal recessive limb-girdle muscular dystrophy.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 42035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCB	NM_000232.5	c.341C>T	p.Ser114Phe	missense_variant	Exon 3 of 6	ENST00000381431.10	NP_000223.1
SGCB	NM_001440519.1	c.131C>T	p.Ser44Phe	missense_variant	Exon 2 of 5		NP_001427448.1
SGCB	NM_001440520.1	c.44C>T	p.Ser15Phe	missense_variant	Exon 4 of 7		NP_001427449.1
SGCB	XM_047416076.1	c.44C>T	p.Ser15Phe	missense_variant	Exon 2 of 5		XP_047272032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10	c.341C>T	p.Ser114Phe	missense_variant	Exon 3 of 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

GnomAD2 exomes AF: 0.000282 AC: 71 AN: 251470 AF XY: 0.000287

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 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

African (AFR) AF: 0.0000598 AC: 2 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000635 AC: 706 AN: 1111498

Other (OTH) AF: 0.000132 AC: 8 AN: 60378

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

African (AFR) AF: 0.000193 AC: 8 AN: 41510

American (AMR) AF: 0.0000656 AC: 1 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000346 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 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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).

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

Nov 11, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Oct 29, 2014

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Oct 29, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 25, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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).

Mar 05, 2015

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:6

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 28, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SGCB: PM3:Very Strong, PM2, PP3, PS3:Supporting

Jul 05, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 18, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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)

Oct 26, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Qualitative or quantitative defects of beta-sarcoglycan Pathogenic:1

Sep 25, 2016

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Inborn genetic diseases Pathogenic:1

Sep 07, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Limb-girdle muscular dystrophy Other:1

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Pathogenic and reported on 04-01-2021 by Invitae. GenomeConnect-InvitaePIN assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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
PhyloP100		9.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.011	D
Vest4		0.84
ClinPred		0.37	T
GERP RS		5.3
Varity_R		0.56
gMVP		0.87
Mutation Taster		=19/81	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs150518260; hg19: chr4-52895932;