chr17-50169169-G-C

Variant names:

• chr17-50169169-G-C
• rs138254713
• NM_000023.4:c.662G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP4_Strong PM3 PM2_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The NM_000023.4: c.662G>C variant in SGCA is a missense variant predicted to cause substitution of arginine by proline at amino acid 221 (p.Arg221Pro). This variant has been detected in at least one individual with autosomal recessive limb girdle muscular dystrophy who was compound heterozygous for the variant and a pathogenic variant (c.585-1G>A, 1.0 pt, Washington University internal clinic data communication) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent expression of alpha-sarcoglycan protein, which is highly specific for SGCA-related LGMD (PP4_Strong, Washington University internal clinic data communication). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.765, which is above the threshold of ≥0.70, evidence that correlates with impact to SGCA function (PP3). In summary, this variant meets the criteria to be classified as Likely 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; 01/07/2025): PM2_Supporting, PP3, PM3, PP4_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA400180670/MONDO:0015152/189

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SGCA NM_000023.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 4.10

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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	c.662G>C	p.Arg221Pro	missense_variant	Exon 6 of 10	ENST00000262018.8	NP_000014.1
SGCA	NM_001135697.3	c.584+597G>C		intron_variant	Intron 5 of 7		NP_001129169.1
SGCA	NR_135553.2	n.698G>C		non_coding_transcript_exon_variant	Exon 6 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8	c.662G>C	p.Arg221Pro	missense_variant	Exon 6 of 10	1	NM_000023.4	ENSP00000262018.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461770 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Jan 07, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000023.4: c.662G>C variant in SGCA is a missense variant predicted to cause substitution of arginine by proline at amino acid 221 (p.Arg221Pro). This variant has been detected in at least one individual with autosomal recessive limb girdle muscular dystrophy who was compound heterozygous for the variant and a pathogenic variant (c.585-1G>A, 1.0 pt, Washington University internal clinic data communication) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent expression of alpha-sarcoglycan protein, which is highly specific for SGCA-related LGMD (PP4_Strong, Washington University internal clinic data communication). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.765, which is above the threshold of ≥0.70, evidence that correlates with impact to SGCA function (PP3). In summary, this variant meets the criteria to be classified as Likely 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; 01/07/2025): PM2_Supporting, PP3, PM3, PP4_Strong. -

Autosomal recessive limb-girdle muscular dystrophy type 2D Uncertain:1

Feb 20, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Oct 10, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.63	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.77		Loss of helix (P = 0.028);
MVP		0.99
MPC		1.3
ClinPred		0.92	D
GERP RS		5.1
Varity_R		0.30
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs138254713; hg19: chr17-48246530;