NM_000023.4:c.518T>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP5

The NM_000023.4(SGCA):c.518T>C(p.Leu173Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,579,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L173L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

SGCA
NM_000023.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:1

Conservation

PhyloP100: 5.11

Publications

2 publications found

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 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

SGCA links:

ENSG00000253730 (HGNC:):

ENSG00000253730 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000023.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-50168506-T-C is Pathogenic according to our data. Variant chr17-50168506-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 281027.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCA	NM_000023.4 link	c.518T>C	p.Leu173Pro	missense_variant	Exon 5 of 10	ENST00000262018.8	NP_000014.1	Q16586-1A0A0S2Z4Q1
SGCA	NM_001135697.3 link	c.518T>C	p.Leu173Pro	missense_variant	Exon 5 of 8		NP_001129169.1	Q16586-2A0A0S2Z4P8
SGCA	NR_135553.2 link	n.554T>C		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 link	c.518T>C	p.Leu173Pro	missense_variant	Exon 5 of 10	1	NM_000023.4	ENSP00000262018.3		Q16586-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00115

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

GnomAD2 exomes

AF:

0.0000464

AC:

AN:

193856

AF XY:

0.0000193

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000998

Gnomad EAS 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:

0.0000259

AC:

AN:

1427708

Hom.:

Cov.:

AF XY:

0.0000255

AC XY:

AN XY:

706736

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32930

American (AMR)

AF:

0.00

AC:

AN:

39334

Ashkenazi Jewish (ASJ)

AF:

0.00110

AC:

AN:

25458

East Asian (EAS)

AF:

0.00

AC:

AN:

38246

South Asian (SAS)

AF:

0.00

AC:

AN:

81436

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51000

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00000548

AC:

AN:

1094456

Other (OTH)

AF:

0.0000508

AC:

AN:

59112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000124

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000415

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D

Pathogenic:6Uncertain:1

Feb 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 173 of the SGCA protein (p.Leu173Pro). This variant is present in population databases (rs143962150, gnomAD 0.1%). This missense change has been observed in individual(s) with sarcoglycanopathy (PMID: 9032047, 18285821; Invitae). 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: 281027). 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%. For these reasons, this variant has been classified as Pathogenic. -

Oct 25, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Sep 24, 2021

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 08, 2021

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000023.2(SGCA):c.518T>C(L173P) is a missense variant classified as likely pathogenic in the context of alpha-sarcoglycanopathy. L173P has been observed in cases with relevant disease (PMID: 18285821, 9393893, 9032047). Functional assessments of this variant are not available in the literature. L173P has been observed in population frequency databases (gnomAD: ASJ 0.09%). In summary, NM_000023.2(SGCA):c.518T>C(L173P) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Feb 08, 2023

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:3

Mar 30, 2023

Athena Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -

Dec 16, 2015

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 15, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in multiple patients who harbored a second SGCA variant with complete a-sarcoglycan deficiency (Duggan et al., 1997; Trabelsi 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: 9032047, 18285821, 24742800, 9192266) -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Nov 08, 2019

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SGCA c.518T>C (p.Leu173Pro) results in a non-conservative amino acid change in the encoded protein sequence. The variant is indicated to be located in a potential glycosylation site (Carrie_1997). 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 4.6e-05 in 193856 control chromosomes (gnomAD). c.518T>C has been reported in the literature in individuals affected with Limb-girdle muscular dystrophy, autosomal recessive (Carrie_1997, Duggan_1997, Trabelsi_2008). Trabelsi_2008 reports the compound heterozygote patient showed decreased protein levels for gamma-sarcoglycan and no protein expression for alpha-sarcoglycan. These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

.;D;D

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.64

T;T;T

M_CAP

Pathogenic

0.83

MetaRNN

Uncertain

0.64

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.1

M;M;.

PhyloP100

5.1

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.5

D;N;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.016

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

0.99

D;D;.

Vest4

0.84

MVP

1.0

MPC

1.3

ClinPred

0.52

GERP RS

4.6

Varity_R

0.78

gMVP

0.96

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over