chr17-50169207-G-A

Position:

chr17-50169207-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4_StrongPM3

This summary comes from the ClinGen Evidence Repository: The NM_000023.4: c.700G>A variant in SGCA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 234 (p.Asp234Asn). This variant has been detected in at least three individuals with autosomal recessive limb girdle muscular dystrophy, including in a homozygous state in two patients (1.0 pt, ClinVar SCV000769867.5 internal data communication) and in unknown phase with a variant classified as at least likely pathogenic (c.100C>T (p.Arg34Cys), 0.25 pts, Washington University internal clinic data communication) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of alpha-sarcoglycan protein in skeletal muscle, which is highly specific for SGCA-related LGMD (PP4_Strong, Washington University internal clinic data communication). The highest minor allele frequency of this variant is 0.0005498 (19/34560 exome chromosomes) in the Admixed American population in gnomAD v2.1.1 (PM2_Supporting, BS1 not met). The computational predictor REVEL gives a score of 0.491 (BP4, PP3 not met). 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)(LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3, PP4_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA246512/MONDO:0015152/189

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

SGCA
NM_000023.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:1U:7

Conservation

PhyloP100: 3.47

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM3

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 link	c.700G>A	p.Asp234Asn	missense_variant	6/10	ENST00000262018.8	NP_000014.1	Q16586-1A0A0S2Z4Q1
SGCA	NM_001135697.3 link	c.584+635G>A		intron_variant			NP_001129169.1	Q16586-2A0A0S2Z4P8
SGCA	NR_135553.2 link	n.736G>A		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8 link	c.700G>A	p.Asp234Asn	missense_variant	6/10	1	NM_000023.4	ENSP00000262018.3		Q16586-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251274

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000550

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000492

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152034

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1Uncertain:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 20, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 234 of the SGCA protein (p.Asp234Asn). This variant is present in population databases (rs760608643, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of SGCA-related conditions (PMID: 32875335). ClinVar contains an entry for this variant (Variation ID: 198031). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SGCA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 11, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 20, 2023	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2023	Observed in a patient with sarcoglycanopathy in published literature; however, no further clinical information is available (Alonso-Prez et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29802408, 32875335) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 13, 2017	- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Jan 07, 2025

The NM_000023.4: c.700G>A variant in SGCA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 234 (p.Asp234Asn). This variant has been detected in at least three individuals with autosomal recessive limb girdle muscular dystrophy, including in a homozygous state in two patients (1.0 pt, ClinVar SCV000769867.5 internal data communication) and in unknown phase with a variant classified as at least likely pathogenic (c.100C>T (p.Arg34Cys), 0.25 pts, Washington University internal clinic data communication) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of alpha-sarcoglycan protein in skeletal muscle, which is highly specific for SGCA-related LGMD (PP4_Strong, Washington University internal clinic data communication). The highest minor allele frequency of this variant is 0.0005498 (19/34560 exome chromosomes) in the Admixed American population in gnomAD v2.1.1 (PM2_Supporting, BS1 not met). The computational predictor REVEL gives a score of 0.491 (BP4, PP3 not met). 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)(LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3, PP4_Strong. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.36

MetaSVM

Pathogenic

1.2

MutationAssessor

Uncertain

2.4

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.79

REVEL

Uncertain

0.49

Sift

Benign

0.51

Sift4G

Benign

0.58

Polyphen

0.88

Vest4

0.44

MutPred

0.44

Loss of helix (P = 0.1299);

MVP

0.98

MPC

1.0

ClinPred

0.26

GERP RS

5.1

Varity_R

0.079

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over