rs28933693

Positions:

• chr17-50167653-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_000023.4(SGCA):​c.229C>T​(p.Arg77Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00047 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: SGCA NM_000023.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:25
• Conservation: PhyloP100: 6.82

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a topological_domain Extracellular (size 266) in uniprot entity SGCA_HUMAN there are 108 pathogenic changes around while only 2 benign (98%) in NM_000023.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-50167653-C-T is Pathogenic according to our data. Variant chr17-50167653-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50167653-C-T is described in Lovd as [Pathogenic]. Variant chr17-50167653-C-T is described in Lovd as [Pathogenic]. Variant chr17-50167653-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCA	NM_000023.4	c.229C>T	p.Arg77Cys	missense_variant	3/10	ENST00000262018.8	NP_000014.1
SGCA	NM_001135697.3	c.229C>T	p.Arg77Cys	missense_variant	3/8		NP_001129169.1
SGCA	NR_135553.2	n.265C>T		non_coding_transcript_exon_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8	c.229C>T	p.Arg77Cys	missense_variant	3/10	1	NM_000023.4	ENSP00000262018	P1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000460 AC: 115 AN: 250208 Hom.: 0 AF XY: 0.000443 AC XY: 60 AN XY: 135374

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00200

Gnomad NFE exome AF: 0.000549

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000473 AC: 692 AN: 1461648 Hom.: 0 Cov.: 32 AF XY: 0.000433 AC XY: 315 AN XY: 727130

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00162

Gnomad4 NFE exome AF: 0.000513

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74468

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000516 Hom.: 0

Bravo AF: 0.000321

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D Pathogenic:13

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 77 of the SGCA protein (p.Arg77Cys). This variant is present in population databases (rs28933693, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with limb girdle muscular dystrophy type 2D (PMID: 7663524, 9032047, 9153448, 9192266, 15298081, 18285821, 18421900, 21856579, 25135358). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9437). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SGCA protein function. Experimental studies have shown that this missense change affects SGCA function (PMID: 16787395, 18252745, 22095924). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. This variant was detected in homozygous state. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000023.2(SGCA):c.229C>T(R77C) is classified as pathogenic in the context of alpha-sarcoglycanopathy. Sources cited for classification include the following: PMID 15736300, 18252745, 9192266 and 18996010. Classification of NM_000023.2(SGCA):c.229C>T(R77C) is based on the following criteria: This is a well-established pathogenic variant in the literature that 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	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The homozgous p.Arg77Cys variant was identified by our study in one individual with Limb-Girdle Muscular Dystrophy. The p.Arg77Cys variant is believed to be pathogenic based on numberous reports by other laboratories in the literature and databases. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 27, 2016	The c.229C>T (p.Arg77Cys) missense variant in the SGCA gene is the most common pathogenic variant reported in individuals affected with autosomal recessive Limb-girdle muscular dystrophy, type 2D (Piccolo et al., 1995; Carrié et al., 1997; Hackman et al., 2005). This variant is located within a mutational hotspot with variants in exon 3 accounting for up to 46% of the affected alleles (Carrié et al., 1997). This variant has been shown to co-segregate with disease in multiple families (Bueno et al., 1995; Kawai et al., 1995). Functional studies have shown this variant results in improper localization of the protein with its retention in the ER as opposed to the plasma membrane (Bartoli et al., 2008). The c.229C>T variant has been reported at low frequency in the control population databases (Exome Sequencing Project [ESP] = 0.081%, 1000 Genomes = 0.3%, and ExAC = 0.154%). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP = 4.53; CADD = 26.5; PolyPhen = 1; SIFT = 0), and multiple reputable diagnostic laboratories report this variant as pathogenic. Therefore, this collective evidence supports the classification of the c.229C>T (p.Arg77Cys) as a recessive Pathogenic variant for Limb-girdle muscular dystrophy, type 2D. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 30, 2022	The p.Arg77Cys variant in SGCA is the most common pathogenic variant in limb girdle muscular dystrophy type 2D (LGMD2D) having been reported in >20 homozygous or compound heterozygous individuals with LGMD2D and segregating in at least 4 affected family members (Bueno 1995 PMID: 8528203, Carrie 1997 PMID: 9192266, Boito 2005 PMID: 12746421, Hackman 2005 PMID: 15736300, Tetreault 2011 PMID: 21856579, Fayssoil 2016 PMID: 21856579, Avila De Salman 2007 PMID: 18421900, Walter 2004 PMID: 15298081, Stehlíková 2014 PMID: 25135358, Trabelsi 2008 PMID: 18285821, Duggan 1997 PMID: 9032047, Piccolo 1995 PMID: 7663524, Eymard 1997 PMID: 9153448). This variant has also been reported in ClinVar (Variation ID 9437) and has been identified in 0.18% (47/24978) of Finnish chromosomes and in 0.05% (69/128290) of European chromosomes by gnomAD (http://gnomAD.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In vitro functional studies provide some evidence that this variant impacts protein function by trapping the protein in the endoplasmic reticulum where it is ultimately degraded (Bartoli 2008 PMID: 18252745, Soheili 2012 PMID: 22095924, Gastaldello 2008 PMID: 18535179, Draviam 2006 PMID: 16787395). 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, PS3_Moderate, PP1_Moderate, PP3. -

not provided Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Dec 07, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2021	Published functional studies demonstrate a damaging effect: absence of the protein at the cell membrane (Draviam et al., 2006; Bartoli et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11391490, 27297959, 27120200, 26934379, 26944168, 31407473, 18421900, 21856579, 22995991, 23989969, 8528203, 7663524, 7657792, 18252745, 22095924, 26916285, 15298081, 24626787, 9436428, 18252746, 9845765, 30919934, 31589614, 32528171, 34106991, 33726816, 15736300, 16787395) -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 12, 2024

Variant summary: SGCA c.229C>T (p.Arg77Cys) 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 0.00046 in 250208 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SGCA causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00046 vs 0.002), allowing no conclusion about variant significance. c.229C>T has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive and has shown to co-segregate with disease in multiple families (examples, Moreira_2003, Tetreault_2011, Vainzof_1999). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 20% of SGCA levels of WT in HER911 cells (Carotti_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29351619, 12566530, 21856579, 10385046). ClinVar contains an entry for this variant (Variation ID: 9437, PATH). 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

Oct 18, 2018

Across a selection of the available literature, the SGCA c.229C>T (p.Arg77Cys) variant has been identified in a homozygous state in at least 28 probands and in a compound heterozygous state in at least eight probands with limb-girdle muscular dystrophy (Bueno et al. 1995; Carrie et al. 1997; Boito et al. 2005; Hackman et al. 2005; Teatreault et al. 2011; Fayssoil et al. 2016). The p.Arg77Cys variant was reported in two of 624 controls and is reported at a frequency of 0.001949 in the European (Finnish) population from the Genome Aggregation Database. Functional studies in human cell lines showed that the p.Arg77Cys variant protein does not localize to the cell membrane, results in impaired assembly of the sarcoglycan complex, and is retained in the endoplasmic reticulum (Bartoli et al. 2008; Gastaldello et al. 2008). Based on the collective evidence, the p.Arg77Cys 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	0.27
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0090	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.89
MVP		0.99
MPC		1.3
ClinPred		0.19	T
GERP RS		4.5
Varity_R		0.62
gMVP		0.92

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

Other links and lift over

dbSNP: rs28933693; hg19: chr17-48245014;