rs387907298

Positions:

• chr17-50168562-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2_Supporting PP1_Strong PP4 PM3 PVS1

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:9
• Conservation: PhyloP100: 2.45

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 Pathogenic. Variant got 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/exons	MANE	Protein	UniProt
SGCA	NM_000023.4	c.574C>T	p.Arg192*	stop_gained	5/10	ENST00000262018.8	NP_000014.1
SGCA	NM_001135697.3	c.574C>T	p.Arg192*	stop_gained	5/8		NP_001129169.1
SGCA	NR_135553.2	n.610C>T		non_coding_transcript_exon_variant	5/9

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000574 AC: 1 AN: 174218 Hom.: 0 AF XY: 0.0000108 AC XY: 1 AN XY: 92336

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: 0.00

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

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000736

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000850 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2011	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Jan 07, 2025

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

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 05, 2017

- -

Abnormality of the musculature Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

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
Eigen	Uncertain	0.42
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.47	N
Vest4		0.68
ClinPred		0.79	D
GERP RS		3.5

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

Publications

LitVar

Other links and lift over

dbSNP: rs387907298; hg19: chr17-48245923;