rs748936034

Positions:

• chr17-50169168-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3 PP4 PM5_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
• Clinical Significance: Uncertain significance reviewed by expert panel P:4 U:7
• Conservation: PhyloP100: 3.39

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 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/exons	MANE	Protein	UniProt
SGCA	NM_000023.4	c.661C>T	p.Arg221Cys	missense_variant	6/10	ENST00000262018.8	NP_000014.1
SGCA	NM_001135697.3	c.584+596C>T		intron_variant			NP_001129169.1
SGCA	NR_135553.2	n.697C>T		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8	c.661C>T	p.Arg221Cys	missense_variant	6/10	1	NM_000023.4	ENSP00000262018.3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152114 Hom.: 0 Cov.: 31

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

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251336 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135854

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 SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461788 Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 30 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152114 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:4 Uncertain:7

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D Pathogenic:3 Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 02, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 03, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 29, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 27, 2024	- -

not provided Pathogenic:1 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 09, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 26, 2024

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. 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 6e-05 in 251336 control chromosomes (gnomAD). 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 reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Stranneheim_2021, Bardhan_2022, Ek_2023). These data indicate that the variant may 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: 28403181, 30764848, 32528171, 33726816, 37273706, 32875335, 35416532). ClinVar contains an entry for this variant (Variation ID: 452720). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Autosomal recessive limb-girdle muscular dystrophy Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Jan 07, 2025

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	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.87		Loss of disorder (P = 0.0179);
MVP		0.99
MPC		1.3
ClinPred		0.57	D
GERP RS		5.1
Varity_R		0.20
gMVP		0.75

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

LitVar

Other links and lift over

dbSNP: rs748936034; hg19: chr17-48246529;