17-50169246-G-A

Position:

chr17-50169246-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5

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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

SGCA
NM_000023.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:18U:1

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 Uncertain_significance. Variant got 5 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167677.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=14}. 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/exons	MANE	Protein
SGCA	NM_000023.4 linkuse as main transcript	c.739G>A	p.Val247Met	missense_variant	6/10	ENST00000262018.8	NP_000014.1
SGCA	NM_001135697.3 linkuse as main transcript	c.584+674G>A		intron_variant			NP_001129169.1
SGCA	NR_135553.2 linkuse as main transcript	n.775G>A		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8 linkuse as main transcript	c.739G>A	p.Val247Met	missense_variant	6/10	1	NM_000023.4	ENSP00000262018	P1	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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:18Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D

Pathogenic:10Uncertain:1

Pathogenic, criteria provided, single submitter	research	James R Lupski Laboratory, Baylor College Of Medicine	Jul 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 08, 2024	Criteria applied: PM3_VSTR,PS3,PM2_SUP,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 21, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 06, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	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). 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: 18535179, 22095924). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 16, 2020	- -
Uncertain significance, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	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). -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 08, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Dec 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 14, 2022	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. -

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

Jun 24, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Dec 03, 2020

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

Sarcoglycanopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 07, 2018

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

MutationTaster

Benign

0.78

D;D;D;D

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