17-50167430-C-T

Variant names:

• chr17-50167430-C-T
• rs758647756
• NM_000023.4:c.100C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PP1 PM2_Supporting PM3_Supporting PM5_Supporting PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000023.4: c.100C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 34 (p.Arg34Cys). This variant has been reported in at least three patients with symptoms of limb girdle muscular dystrophy (PMID:7663524, 21031578; Washington University internal clinic data communication), including in a homozygous state in one patient from a consanguineous family (0.25 pts) and confirmed in trans with a SGCA variant not yet curated by the VCEP and considered VUS (0.25 pts) (PM3_Supporting). At least one patient with this variant displayed progressive muscle weakness and significantly reduced alpha-sarcoglycan protein expression, which is highly specific for SGCA-related LGMD (PP4_Strong; PMID:7663524, 21031578, Washington University internal clinic data communication). The variant has also been reported to segregate with autosomal recessive limb girdle muscular dystrophy in one affected family member (PP1; PMID:7663524). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 (1/113724 alleles) in the European (non-Finnish) population, which is lower than the ClinGen LGMD VCEP threshold (0.00009) for PM2_Supporting, meeting this criterion (PM2_Supporting). Another missense variant at the same codon, c.101G>A (p.Arg34His), has been classified as likely pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PM5_Supporting). 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; 01/09/2025): PM3_Supporting, PP4_Strong, PM5_Supporting, PP3, PM2_Supporting, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210084/MONDO:0015152/189

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SGCA NM_000023.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 1.81
• Publications: 4 publications found

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, STRONG Submitted by: ClinGen, PanelApp Australia
• autosomal recessive limb-girdle muscular dystrophy type 2D

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

ENSG00000253730 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 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.
• PM5: 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_000023.4. 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
	SGCA	NM_000023.4	MANE Select	c.100C>T	p.Arg34Cys	missense	Exon 2 of 10	NP_000014.1	A0A0S2Z4Q1
	SGCA	NM_001135697.3		c.100C>T	p.Arg34Cys	missense	Exon 2 of 8	NP_001129169.1	A0A0S2Z4P8
	SGCA	NR_135553.2		n.136C>T		non_coding_transcript_exon	Exon 2 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCA	ENST00000262018.8	TSL:1 MANE Select	c.100C>T	p.Arg34Cys	missense	Exon 2 of 10	ENSP00000262018.3	Q16586-1
	SGCA	ENST00000344627.10	TSL:1	c.100C>T	p.Arg34Cys	missense	Exon 2 of 8	ENSP00000345522.6	Q16586-2
	SGCA	ENST00000952408.1		c.190C>T	p.Arg64Cys	missense	Exon 2 of 10	ENSP00000622467.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251428 AF XY: 0.00000736

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

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: 0.0000153 AC: 17 AN: 1112004

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

African (AFR) AF: 0.0000241 AC: 1 AN: 41436

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000317 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2D (6)
2	-	-	not provided (2)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.90		Loss of methylation at R34 (P = 0.0204)
MVP		1.0
MPC		1.2
ClinPred		0.96	D
GERP RS		3.4
Varity_R		0.16
gMVP		0.82
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs758647756; hg19: chr17-48244791; COSMIC: COSV100006938; COSMIC: COSV100006938;