4-52028899-G-C

Variant names:

• chr4-52028899-G-C
• rs28936383
• NM_000232.5:c.452C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP1_Moderate PP3 PP4 PS3_Moderate PM2_Supporting PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000232.5: c.452C>G variant in SGCB is a missense variant predicted to cause substitution of threonine by arginine at amino acid 151 p.(Thr151Arg). This variant has been detected in at least five individuals with signs of limb girdle muscular dystrophy, including in a homozygous state (1.0 pt; PMID:30564623, 21480868, 7581448) and confirmed in trans with a pathogenic variant (c.271C>T p.(Arg91Cys), 1.0 pt, PMID:9565988) (PM3_Strong). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy (PP4). The variant has also been shown to segregate with autosomal recessive LGMD in at least 5 affected family members in families from the Plain community in southern Indiana and has been proposed as a founder variant for this population (PP1_Moderate; PMID:7581448, 9565988, 28615891, 3083835). The minor allele frequency of this variant is 0.00006498 for European (non-Finnish) chromosomes in gnomAD v2.1.1 (1/15390), which is lower than the LGMD VCEP threshold (<0.00009) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays of membrane localization in HEK293 and HER-911 cells showed that expression of p.Thr151Arg in β-sarcoglycan disrupted localization of both the β-sarcoglycan subunit and the sarcoglycan complex to the plasma membrane, indicating an impact of the variant on protein function (PMID:37317968, 22095924) (PS3_Moderate). The computational predictor REVEL gives a score of 0.87, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to SGCB function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Strong, PP4, PP1_Moderate, PM2_Supporting, PS3_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA119849/MONDO:0015152/184

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SGCB NM_000232.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 8.00
• Publications: 16 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 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000232.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	NM_000232.5	MANE Select	c.452C>G	p.Thr151Arg	missense	Exon 4 of 6	NP_000223.1
	SGCB	NM_001440519.1		c.242C>G	p.Thr81Arg	missense	Exon 3 of 5	NP_001427448.1
	SGCB	NM_001440520.1		c.155C>G	p.Thr52Arg	missense	Exon 5 of 7	NP_001427449.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	ENST00000381431.10	TSL:1 MANE Select	c.452C>G	p.Thr151Arg	missense	Exon 4 of 6	ENSP00000370839.6
	SGCB	ENST00000506357.5	TSL:5	n.*234C>G		non_coding_transcript_exon	Exon 5 of 5	ENSP00000421235.1
	SGCB	ENST00000514133.1	TSL:5	n.*247C>G		non_coding_transcript_exon	Exon 4 of 4	ENSP00000425818.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152034 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461426 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727054

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111672

Other (OTH) AF: 0.0000166 AC: 1 AN: 60376

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152034 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74224

African (AFR) AF: 0.00 AC: 0 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2E Pathogenic:6

Nov 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Feb 20, 2015

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Dec 05, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 151 of the SGCB protein (p.Thr151Arg). This variant is present in population databases (rs28936383, gnomAD 0.007%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 7581448, 9565988, 21480868). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8712). 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.

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: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:22095924) (PMID:9565988).

Dec 21, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Jan 09, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000232.5: c.452C>G variant in SGCB is a missense variant predicted to cause substitution of threonine by arginine at amino acid 151 p.(Thr151Arg). This variant has been detected in at least five individuals with signs of limb girdle muscular dystrophy, including in a homozygous state (1.0 pt; PMID: 30564623, 21480868, 7581448) and confirmed in trans with a pathogenic variant (c.271C>T p.(Arg91Cys), 1.0 pt, PMID: 9565988) (PM3_Strong). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy (PP4). The variant has also been shown to segregate with autosomal recessive LGMD in at least 5 affected family members in families from the Plain community in southern Indiana and has been proposed as a founder variant for this population (PP1_Moderate; PMID: 7581448, 9565988, 28615891, 3083835). The minor allele frequency of this variant is 0.00006498 for European (non-Finnish) chromosomes in gnomAD v2.1.1 (1/15390), which is lower than the LGMD VCEP threshold (<0.00009) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays of membrane localization in HEK293 and HER-911 cells showed that expression of p.Thr151Arg in β-sarcoglycan disrupted localization of both the β-sarcoglycan subunit and the sarcoglycan complex to the plasma membrane, indicating an impact of the variant on protein function (PMID: 37317968, 22095924) (PS3_Moderate). The computational predictor REVEL gives a score of 0.87, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to SGCB function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Strong, PP4, PP1_Moderate, PM2_Supporting, PS3_Moderate, PP3.

not provided Pathogenic:1

Sep 14, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.0
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.65		Loss of ubiquitination at K152 (P = 0.0503)
MVP		1.0
MPC		0.35
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.55
gMVP		0.73
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28936383; hg19: chr4-52895065;