17-50170245-C-T

Position:

chr17-50170245-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3_StrongPP3PP1PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000023.4: c.850C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 284 (p.Arg284Cys). This variant has been detected in at least five individuals with autosomal recessive limb girdle muscular dystrophy. Of those individuals, one was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (c.241C>T p.(Arg81Cys), 1 pt, PMID:17994539), and two were homozygous for the variant (1 pt, PMID:26404900, 26453141) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic variant in SGCA displayed progressive limb girdle muscle weakness and significantly reduced or absent alpha-sarcoglycan protein expression, which is highly specific for SGCA-related LGMD (PP4_Strong; UCSD internal clinic data communication, PMID:17994539). In addition, the variant has been reported to segregate with autosomal recessive limb girdle muscular dystrophy in one affected family member (PP1; PMID:17994539). The minor allele frequency for this variant is 0.0002205 in the European (non-Finnish) population of gnomAD v3.1.2 (15/68028 genome chromosomes), which exceeds the LGMD VCEP threshold of 0.00009 for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.754, which is above the threshold of 0.7, evidence that correlates with impact to SGCA function (PP3). 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; 01/09/2025): PM3_Strong, PP4_Strong, PP1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120431/MONDO:0015152/189

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000093 ( 0 hom. )

Consequence

SGCA
NM_000023.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:17

Conservation

PhyloP100: 1.54

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:

SGCA (HGNC:):

SGCA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM3

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCA	NM_000023.4 linkuse as main transcript	c.850C>T	p.Arg284Cys	missense_variant	7/10	ENST00000262018.8	NP_000014.1	Q16586-1A0A0S2Z4Q1
SGCA	NM_001135697.3 linkuse as main transcript	c.585-395C>T		intron_variant			NP_001129169.1	Q16586-2A0A0S2Z4P8
SGCA	NR_135553.2 linkuse as main transcript	n.784-395C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8 linkuse as main transcript	c.850C>T	p.Arg284Cys	missense_variant	7/10	1	NM_000023.4	ENSP00000262018.3		Q16586-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000151

AC:

AN:

251442

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000930

AC:

136

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000976

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000728

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000144

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000193

Hom.:

Bravo

AF:

0.000162

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000415

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 13, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 284 of the SGCA protein (p.Arg284Cys). This variant is present in population databases (rs137852623, gnomAD 0.08%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy type 2D and is one of the most common causes (PMID: 9032047, 9192266, 18285821, 18421900, 25135358, 26404900, 26453141). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 9439). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SGCA function (PMID: 22095924). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000023.2(SGCA):c.850C>T(R284C) is classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency and may be associated with the mild form of this disease.. Sources cited for classification include the following: PMID 22095924, 12746421, 9585331 and 17994539. Classification of NM_000023.2(SGCA):c.850C>T(R284C) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 31, 2020	The p.Arg284Cys variant in SGCA has been reported in the homozygous or compound heterozygous state in >20 individuals with autosomal recessive limb-girdle muscular dystrophy type 2D and segregated with disease in at least 4 affected individuals (Angelini 1998, Avila De Salman 2007, Boito 2003, Duggan 1997, Guglieri 2008, Klinge 2008, Magri 2015, Stehlikova 2014, Tarnopolsky 2015, Trabelsi 2008, Soheili 2012). This variant is typically associated with a more mild course of disease, particularly in the homozygous state, which is consistent with in vitro functional studies (Soheili 2012). It has also been identified in 0.077% (8/10368) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 9439). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive limb-girdle muscular dystrophy type 2D. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Moderate, PS3_Supporting. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1998	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 12075495, 18285821, 9585331, 27297959, 33458577, 34440373, 18421900, 26453141, 22095924, 11693784, 17994539, 9032047, 9192266, 9153448, 10842281, 12746421, 12566530, 30218921, 29382405, 29792937, 18996010, 30564623, 30919934, 31517061, 34426522, 31589614, 32140910, 32528171, 31980526) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	SGCA: PM3:Very Strong, PM2, PS3:Supporting -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen	Jan 09, 2025	The NM_000023.4: c.850C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 284 (p.Arg284Cys). This variant has been detected in at least five individuals with autosomal recessive limb girdle muscular dystrophy. Of those individuals, one was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (c.241C>T p.(Arg81Cys), 1 pt, PMID: 17994539), and two were homozygous for the variant (1 pt, PMID: 26404900, 26453141) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic variant in SGCA displayed progressive limb girdle muscle weakness and significantly reduced or absent alpha-sarcoglycan protein expression, which is highly specific for SGCA-related LGMD (PP4_Strong; UCSD internal clinic data communication, PMID: 17994539). In addition, the variant has been reported to segregate with autosomal recessive limb girdle muscular dystrophy in one affected family member (PP1; PMID: 17994539). The minor allele frequency for this variant is 0.0002205 in the European (non-Finnish) population of gnomAD v3.1.2 (15/68028 genome chromosomes), which exceeds the LGMD VCEP threshold of 0.00009 for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.754, which is above the threshold of 0.7, evidence that correlates with impact to SGCA function (PP3). 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; 01/09/2025): PM3_Strong, PP4_Strong, PP1, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 11, 2019	Variant summary: SGCA c.850C>T (p.Arg284Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251442 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in SGCA causing Limb-girdle muscular dystrophy (autosomal recessive) (0.00015 vs 0.002), allowing no conclusion about variant significance. c.850C>T has been reported in the literature in multiple individuals affected with Limb-girdle muscular dystrophy (e.g. Guglieri_2008). These data indicate that the variant is very likely to be associated with disease. In functional studies, this variant showed significantly reduced ATPase activity. The authors of this study suggested that this could be due to partially trapped mutant protein in the endoplasmic reticulum. Five ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Abnormality of the musculature

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Sarcoglycanopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jul 14, 2017

The SGCA c.850C>T (p.Arg284Cys) variant has been reported in six studies in which it is found in a total of 11 individuals with varying levels of alpha-sarcoglycan deficiency, including seven individuals in a compound heterozygous state, three individuals in a homozygous state, and one individual in a heterozygous state (Duggan et al. 1997; Angelini et al. 1998; Boito et al. 2003; Avila de Salman et al. 2007; Klinge et al. 2008; Stehlikova et al. 2014). The p.Arg284Cys variant was absent from over 300 control samples and is reported at a frequency of 0.00018 in the South Asian population of the Exome Aggregation Consortium. Immunohistochemistry studies have revealed a decrease in SGCA expression in individuals that carry the p.Arg284Cys variant (Angelini et al. 1998; Boito et al. 2003; Avila De Salman et al. 2007), although expression levels may vary. Based on the collective evidence, the p.Arg284Cys variant is classified as pathogenic for alpha-sarcoglycanopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.89

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-5.6

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.86

MVP

1.0

MPC

1.2

ClinPred

0.29

GERP RS

5.8

Varity_R

0.43

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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