NM_000232.5:c.271C>T

Variant names:

• chr4-52029836-G-A
• rs555514820
• NM_000232.5:c.271C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP1_Moderate PP4 PP3 PS3_Moderate PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000232.5: c.271C>T variant in SGCB is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 91 p.(Arg91Cys). This variant has been detected in at least five individuals with signs of limb girdle muscular dystrophy, including in a homozygous state in families from the Plain community (0.5 pts; PMID:35416532, 9565988) and confirmed in trans with a pathogenic variant in two cases (c.85A>T p.(Arg29Ter), 2.0 pts, PMID:17994539, 11369190) (PM3_Strong). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy and displayed severely reduced expression of β-sarcoglycan in skeletal muscle, which is highly specific for SGCB-related LGMD (PMID:11369190); however, the presence of potentially diagnostic variants in all of the other three sarcoglycan genes was not ruled out (PP4). The variant has also been reported to segregate with LGMD in at least two affected family members from two nuclear Plain community families (PP1_Moderate; PMID:9565988). The filtering allele frequency of this variant is 0.0002533 for South Asian exome chromosomes by gnomAD v2.1.1 (the upper threshold of the 95% CI of 3/30614), which is higher than the ClinGen LGMD VCEP threshold (<0.00009) for PM2_Supporting and therefore this criterion is not met. Expression of p.Arg91Cys in β-sarcoglycan in vitro has been shown to disrupt localization of the sarcoglycan complex to the plasma membrane, indicating an impact of the c.271C>T p.(Arg91Cys) variant on protein function (PMID:37317968) (PS3_Moderate). The computational predictor REVEL gives a score of 0.95, 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, PS3_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA2918445/MONDO:0015152/184

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SGCB NM_000232.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 7.83
• Publications: 7 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, STRONG Submitted by: ClinGen, PanelApp Australia
• autosomal recessive limb-girdle muscular dystrophy type 2E

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	NM_000232.5	MANE Select	c.271C>T	p.Arg91Cys	missense	Exon 3 of 6	NP_000223.1	Q5U0N0
	SGCB	NM_001440520.1		c.-27C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 7	NP_001427449.1
	SGCB	NM_001440519.1		c.61C>T	p.Arg21Cys	missense	Exon 2 of 5	NP_001427448.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	ENST00000381431.10	TSL:1 MANE Select	c.271C>T	p.Arg91Cys	missense	Exon 3 of 6	ENSP00000370839.6	Q16585-1
	SGCB	ENST00000899666.1		c.271C>T	p.Arg91Cys	missense	Exon 3 of 6	ENSP00000569725.1
	SGCB	ENST00000912466.1		c.271C>T	p.Arg91Cys	missense	Exon 3 of 5	ENSP00000582525.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152034 Hom.: 0 Cov.: 32

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: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251452 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461504 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 727088

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

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111694

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74376

African (AFR) AF: 0.00 AC: 0 AN: 41522

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000343 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2E (7)
2	-	-	Autosomal recessive limb-girdle muscular dystrophy (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.82		Gain of catalytic residue at V89 (P = 0.0889)
MVP		0.99
MPC		0.45
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.59
gMVP		0.87
Mutation Taster		=3/97	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: rs555514820; hg19: chr4-52896002;