chr17-50168562-C-T

Variant names:

• chr17-50168562-C-T
• rs387907298
• NM_000023.4:c.574C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PP4 PM2_Supporting PP1_Strong PVS1 PM3

This summary comes from the ClinGen Evidence Repository: The NM_000023.4: c.574C>T p.(Arg192Ter) variant in SGCA is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5/10, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in four individuals with autosomal recessive limb girdle muscular dystrophy, all of whom were homozygous for the variant. Consanguinity was reported in one of the four families (1.0 pt, PMID:26934379, 22303798; PM3). The variant has also been reported to co-segregate with autosomal recessive limb girdle muscular dystrophy in eight affected meioses from four families (PP1_Strong; PMID:26934379, 22303798). At least one patient with this variant displayed progressive limb girdle muscle weakness and reduced expression of alpha-sarcoglycan protein in skeletal muscle, which is specific for SGCA-related LGMD (PP4; PMID:26934379) (capped with PP1_Strong). The highest population minor allele frequency of this variant in gnomAD v2.1.1 is 0.00001 (1/71080 alleles) in the European (non-Finnish) population, which is lower than the VCEP threshold (0.00009) for PM2_Supporting, meeting this criterion (PM2_Supporting). 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; 01/07/2025): PVS1, PP1_Strong, PP4, PM3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA130100/MONDO:0015152/189

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: SGCA NM_000023.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 2.45
• Publications: 12 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.
• 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.574C>T	p.Arg192*	stop_gained	Exon 5 of 10	NP_000014.1	A0A0S2Z4Q1
	SGCA	NM_001135697.3		c.574C>T	p.Arg192*	stop_gained	Exon 5 of 8	NP_001129169.1	A0A0S2Z4P8
	SGCA	NR_135553.2		n.610C>T		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCA	ENST00000262018.8	TSL:1 MANE Select	c.574C>T	p.Arg192*	stop_gained	Exon 5 of 10	ENSP00000262018.3	Q16586-1
	SGCA	ENST00000344627.10	TSL:1	c.574C>T	p.Arg192*	stop_gained	Exon 5 of 8	ENSP00000345522.6	Q16586-2
	SGCA	ENST00000952408.1		c.664C>T	p.Arg222*	stop_gained	Exon 5 of 10	ENSP00000622467.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000574 AC: 1 AN: 174218 AF XY: 0.0000108

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: 0.0000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000566 AC: 8 AN: 1414270 Hom.: 0 Cov.: 33 AF XY: 0.00000715 AC XY: 5 AN XY: 698926

African (AFR) AF: 0.00 AC: 0 AN: 32456

American (AMR) AF: 0.00 AC: 0 AN: 37456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25288

East Asian (EAS) AF: 0.00 AC: 0 AN: 37336

South Asian (SAS) AF: 0.00 AC: 0 AN: 80346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00000736 AC: 8 AN: 1086808

Other (OTH) AF: 0.00 AC: 0 AN: 58634

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000850 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2D (7)
1	-	-	Abnormality of the musculature (1)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.47	N
PhyloP100		2.5
Vest4		0.68
ClinPred		0.79	D
GERP RS		3.5
Mutation Taster		=4/196	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: rs387907298; hg19: chr17-48245923;