rs143570936

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_000023.4(SGCA):c.739G>A(p.Val247Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,612,294 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

SGCA
NM_000023.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 1.52

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 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 17-50169246-G-A is Pathogenic according to our data. Variant chr17-50169246-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 167677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50169246-G-A is described in Lovd as [Pathogenic]. Variant chr17-50169246-G-A is described in Lovd as [Pathogenic]. Variant chr17-50169246-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCA	NM_000023.4 link	c.739G>A	p.Val247Met	missense_variant	Exon 6 of 10	ENST00000262018.8	NP_000014.1	Q16586-1A0A0S2Z4Q1
SGCA	NM_001135697.3 link	c.584+674G>A		intron_variant	Intron 5 of 7		NP_001129169.1	Q16586-2A0A0S2Z4P8
SGCA	NR_135553.2 link	n.775G>A		non_coding_transcript_exon_variant	Exon 6 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8 link	c.739G>A	p.Val247Met	missense_variant	Exon 6 of 10	1	NM_000023.4	ENSP00000262018.3		Q16586-1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000112

AC:

AN:

250368

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135388

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000580

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:

0.000221

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000214

AC:

312

AN:

1460130

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

147

AN XY:

726060

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000258

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000191

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000191

Hom.:

Bravo

AF:

0.000208

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D

Pathogenic:11

Dec 21, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 247 of the SGCA protein (p.Val247Met). This variant is present in population databases (rs143570936, gnomAD 0.02%). This missense change has been observed in individual(s) with limb girdle muscular dystrophy type 2D (PMID: 7663524, 9192266, 18285821, 25135358, 25214167, 26404900, 26453141, 26934379). 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: 167677). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 18535179, 22095924). For these reasons, this variant has been classified as Pathogenic. -

Jul 01, 2019

James R Lupski Laboratory, Baylor College Of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 06, 2020

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000023.2(SGCA):c.739G>A(V247M) is classified as likely pathogenic in the context of alpha-sarcoglycanopathy. Sources cited for classification include the following: PMID 22095924, 24565866, 18535179, 18996010, 7663524, 17994539 and 25135358. Classification of NM_000023.2(SGCA):c.739G>A(V247M) 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. -

Feb 08, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2020

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Val247Met variant in SGCA was identified by our study in two unrelated individuals in the compound heterozygous state, with another pathogenic variant, in individuals with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.02379% (30/126108) of European (non-Finnish) chromosomes, in 0.005816% (2/34386) of Latino chromosomes, and 0.004167% (1/23998) of African chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs143570936). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The p.Val247Met variant in SGCA has been reported in many individuals with Limb-Girdle Muscular Dystrophy and segregated with disease in 2 affected relatives from 1 family (PMID: 15298081). the presence of this variant in combination with a reported pathogenic variant and in an individual with Limb-Girdle Musclar Dystrophy increases the likelihood that the p.Val247Met variant is pathogenic. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Functional assays provide some evidence that the p.Val247Met variant may impact protein function by reducing protein localization to the membrane and expression in the muscle tissue (PMID: 15298081, 22095924). However, these types of assays may not accurately represent biological function. This variant has also been reported pathogenic and likely pathogenic in ClinVar (Variation ID: 167677). In summary, the p.Val247Met variant is pathogenic based off of our findings, multiple reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PS3, PM3_Strong, PM2, PP1 (Richards 2015). -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 08, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM3_VSTR,PS3,PM2_SUP,PP3 -

not provided

Pathogenic:5

Dec 05, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect as V247M results in the degradation of the SGCA protein through the ERAD-LM pathway prior to leaving the endoplasmic reticulum (Bianchini et al., 2014); This variant is associated with the following publications: (PMID: 18285821, 26934379, 7663524, 34598035, 22095924, 26453141, 10942431, 18996010, 17994539, 15298081, 29351619, 30919934, 31517061, 31407473, 34426522, 31589614, 31953240, 25214167, 32528171, 33726816, 33458577, 24565866) -

Feb 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 14, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to reduce protein expression and interfere with membrane localization (PMID: 18535179, 22095924). 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. -

Dec 07, 2018

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Jun 24, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SGCA c.739G>A (p.Val247Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 250728 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in SGCA causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00011 vs 0.002), allowing no conclusion about variant significance. c.739G>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive, including homozygotes (Piccolo_1995, Soheili_2012, Magri_2015). These data indicate that the variant is very likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and this variant results in dramatic reduction of the mutated protein and the absence of the sarcoglycan complex from the cell surface (Gastaldello_2008, Soheili_2012, Bianchini_2014). Fifteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

See cases

Pathogenic:1

Dec 03, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3, PS4, PM2, PM3 -

Sarcoglycanopathy

Pathogenic:1

Sep 07, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of available literature, the SGCA c.739G>A (p.Val247Met) variant has been identified in a homozygous state in two probands, in a compound heterozygous state in at least 11 probands, and in a heterozygous state in three probands in whom a second variant was not identified (Piccolo et al. 1995; Eymard et al. 1997; Crosbie et al. 2000; Moreira et al. 2003; Klinge et al. 2008; Guglieri et al. 2008; Trabelsi et al. 2008; Mendell et al. 2010). Control data are not available for this variant, which is reported at a frequency of 0.000238 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies in HEK293 cells demonstrated that the p.Val247Met variant increases ubiquitination and degradation of alpha-sarcoglycan via the E3 ligase HRD1, and inhibition of this pathway in myotubes derived from a limb-girdle muscular dystrophy type 2D patient carrying the p.Val247Met variant rescued alpha-sarcoglycan expression at the cell membrane (Bianchini et al. 2014). Based on the collective evidence, the p.Val247Met 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

0.28

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.33

MetaRNN

Uncertain

0.65

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.26

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.020

Polyphen

0.97

Vest4

0.40

MVP

0.98

MPC

0.99

ClinPred

0.41

GERP RS

3.9

Varity_R

0.19

gMVP

0.57

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

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