rs748936034

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3PP4PM5_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000023.4: c.661C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 221 (p.Arg221Cys). This variant has been identified in at least five individuals with clinical signs of limb girdle muscular dystrophy (PMID:35416532, 28403181, 30564623; LOVD SGCA_000169) (PP4). The highest minor allele frequency of this variant is 0.0002940 (9/30612 exome chromosomes) in the South Asian population of gnomAD v2.1.1, which is greater than the ClinGen LGMD VCEP threshold (0.00009) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.787, which is above the VCEP threshold of ≥0.70, evidence that correlates with impact to SGCA function (PP3). In addition, another missense variant at the same codon, c.662G>C (p.Arg221Pro), has been classified as likely pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5_Supporting). In summary, this variant cannot be classified as pathogenic nor benign at this time and remains a variant of uncertain significance 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; 01/07/2025): PP4, PP3, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8643859/MONDO:0015152/189

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

SGCA
NM_000023.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:5U:6

Conservation

PhyloP100: 3.39

Publications

2 publications found

Variant links:

Genes affected

SGCA (HGNC:10805): (sarcoglycan alpha) This gene encodes a component of the dystrophin-glycoprotein complex (DGC), which is critical to the stability of muscle fiber membranes and to the linking of the actin cytoskeleton to the extracellular matrix. Its expression is thought to be restricted to striated muscle. Mutations in this gene result in type 2D autosomal recessive limb-girdle muscular dystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

SGCA 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 2D
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine, Orphanet

SGCA links:

ENSG00000253730 (HGNC:):

ENSG00000253730 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM5

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
SGCA	NM_000023.4 link	c.661C>T	p.Arg221Cys	missense_variant	Exon 6 of 10	ENST00000262018.8	NP_000014.1	Q16586-1A0A0S2Z4Q1
SGCA	NR_135553.2 link	n.697C>T		non_coding_transcript_exon_variant	Exon 6 of 9
SGCA	NM_001135697.3 link	c.584+596C>T		intron_variant	Intron 5 of 7		NP_001129169.1	Q16586-2A0A0S2Z4P8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8 link	c.661C>T	p.Arg221Cys	missense_variant	Exon 6 of 10	1	NM_000023.4	ENSP00000262018.3		Q16586-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152114

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:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000597

AC:

AN:

251336

AF XY:

0.0000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461788

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000336

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111972

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000827

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:5Uncertain:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D

Pathogenic:3Uncertain:3

Mar 03, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 02, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Mar 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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 221 of the SGCA protein (p.Arg221Cys). This variant is present in population databases (rs748936034, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (PMID: 28403181, 32528171; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 452720). 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 expected to disrupt SGCA protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

May 29, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 10, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 27, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1Uncertain:2

Jan 09, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 12, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R221C variant in the SGCA gene has been reported previously in the compound heterozygous state, with a second SGCA missense variant, in a Chinese individual with childhood-onset muscle weakness, myalgia, cardiac abnormalities, and elevated creatine kinase (Yu et al., 2017). The R221C variant is observed in 9/30,778 (0.029%) alleles from individuals of South Asian background, in large population cohorts (Lek et al., 2016). The R221C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R221C as a variant of uncertain significance. -

Mar 22, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1Uncertain:1

May 22, 2025

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SGCA c.661C>T (p.Arg221Cys) results in a non-conservative amino acid change located in the Sarcoglycan alpha/epsilon second domain (IPR048347) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 6e-05 in 251336 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SGCA causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (6e-05 vs 0.002), allowing no conclusion about variant significance. c.661C>T has been observed in individual(s) affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Stranneheim_2021, Bardhan_2022, Ek_2023, internal data). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32875335, 35416532, 37273706, 33726816, 32528171, 30764848, 28403181). ClinVar contains an entry for this variant (Variation ID: 452720). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jan 07, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000023.4: c.661C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 221 (p.Arg221Cys). This variant has been identified in at least five individuals with clinical signs of limb girdle muscular dystrophy (PMID: 35416532, 28403181, 30564623; LOVD SGCA_000169) (PP4). The highest minor allele frequency of this variant is 0.0002940 (9/30612 exome chromosomes) in the South Asian population of gnomAD v2.1.1, which is greater than the ClinGen LGMD VCEP threshold (0.00009) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.787, which is above the VCEP threshold of ≥0.70, evidence that correlates with impact to SGCA function (PP3). In addition, another missense variant at the same codon, c.662G>C (p.Arg221Pro), has been classified as likely pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5_Supporting). In summary, this variant cannot be classified as pathogenic nor benign at this time and remains a variant of uncertain significance 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; 01/07/2025): PP4, PP3, PM5_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

PhyloP100

3.4

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.68

MutPred

0.87

Loss of disorder (P = 0.0179);

MVP

0.99

MPC

1.3

ClinPred

0.57

GERP RS

5.1

Varity_R

0.20

gMVP

0.75

Mutation Taster

=30/70

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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rs748936034

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over