rs387907298

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 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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCA	NM_000023.4	c.574C>T	p.Arg192*	stop_gained	Exon 5 of 10	ENST00000262018.8	NP_000014.1
SGCA	NM_001135697.3	c.574C>T	p.Arg192*	stop_gained	Exon 5 of 8		NP_001129169.1
SGCA	NR_135553.2	n.610C>T		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8	c.574C>T	p.Arg192*	stop_gained	Exon 5 of 10	1	NM_000023.4	ENSP00000262018.3

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

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D Pathogenic:7

Jan 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Feb 08, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 28, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 24, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg192*) in the SGCA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SGCA are known to be pathogenic (PMID: 9192266). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with limb-girdle muscular dystrophy (PMID: 22303798, 26934379). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37202). For these reasons, this variant has been classified as Pathogenic.

Mar 07, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Jan 07, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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.

not provided Pathogenic:1

Dec 05, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Abnormality of the musculature Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	47
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.0	.;.;.
MetaRNN	Benign	0.0	.;.;.
MutationAssessor	Benign	0.0	.;.;.
PhyloP100		2.5
PROVEAN	Benign	0.0	.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.
Sift4G	Pathogenic	0.0	.;.;.
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;