rs555514820

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3_StrongPS3_ModeratePP1_ModeratePP4PP3

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

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: 7.83

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCB	NM_000232.5 link	c.271C>T	p.Arg91Cys	missense_variant	Exon 3 of 6	ENST00000381431.10	NP_000223.1	Q16585-1Q5U0N0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10 link	c.271C>T	p.Arg91Cys	missense_variant	Exon 3 of 6	1	NM_000232.5	ENSP00000370839.6		Q16585-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152034

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251452

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135896

show subpopulations

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 SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461504

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000332

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2E

Pathogenic:7

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 16, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 91 of the SGCB protein (p.Arg91Cys). This variant is present in population databases (rs555514820, gnomAD 0.01%). This missense change has been observed in individuals with limb-girdle muscular dystrophy (PMID: 9565988, 17994539). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 499193). 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 does not substantially affect SGCB function (PMID: 22095924). This variant disrupts the p.Arg91 amino acid residue in SGCB. Other variant(s) that disrupt this residue have been observed in individuals with SGCB-related conditions (PMID: 8968749, 9631401), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Feb 19, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

A known missense variant, c.271C>T in exon 3 of SGCB was identified in a compound heterozygous state in the proband. The known missense variant, c.271C>T was found in a heterozygous state in the father (Cagliani, R., et al., 2001). It is identified in 19 heterozygous individuals and no homozygous individuals in gnomAD v4.1.0. This variant is also seen in five individuals within our in-house database of 3557 exomes. It is classified as pathogenic in the ClinVar database (ClinVar ID: VCV000499193.23) and is associated with autosomal recessive limb girdle muscular dystrophy -

Apr 17, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:2

Oct 04, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SGCB c.271C>T (p.Arg91Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251452 control chromosomes. c.271C>T has been reported in the literature as a compound heterozygous or homozygous genotype in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Duclos_1998, Guglieri_2008, Magri_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function by confocal immunofluorescence analysis of non-permeabilized cells and classifies this variant as a class I - mutation that did not affect the membrane localization of Sarcoglycan B (Soheilli_2012). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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.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. -

Inborn genetic diseases

Pathogenic:1

Feb 01, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Sep 14, 2018

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.6

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.96

MutPred

0.82

Gain of catalytic residue at V89 (P = 0.0889);

MVP

0.99

MPC

0.45

ClinPred

0.98

GERP RS

5.3

Varity_R

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over