chr13-23320639-T-C

Position:

chr13-23320639-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000231.3(SGCG):c.581T>C(p.Leu194Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000242 in 1,529,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

SGCG
NM_000231.3 missense, splice_region

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 6.86

Variant links:

Genes affected

SGCG (HGNC:10809): (sarcoglycan gamma) This gene encodes gamma-sarcoglycan, one of several sarcolemmal transmembrane glycoproteins that interact with dystrophin. The dystrophin-glycoprotein complex (DGC) spans the sarcolemma and is comprised of dystrophin, syntrophin, alpha- and beta-dystroglycans and sarcoglycans. The DGC provides a structural link between the subsarcolemmal cytoskeleton and the extracellular matrix of muscle cells. Defects in the encoded protein can lead to early onset autosomal recessive muscular dystrophy, in particular limb-girdle muscular dystrophy, type 2C (LGMD2C). [provided by RefSeq, Oct 2008]

SGCG links:

SACS (HGNC:10519): (sacsin molecular chaperone) This gene encodes the sacsin protein, which includes a UbL domain at the N-terminus, a DnaJ domain, and a HEPN domain at the C-terminus. The gene is highly expressed in the central nervous system, also found in skin, skeletal muscles and at low levels in the pancreas. This gene includes a very large exon spanning more than 12.8 kb. Mutations in this gene result in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. The authors of a publication on the effects of siRNA-mediated sacsin knockdown concluded that sacsin protects against mutant ataxin-1 and suggest that "the large multi-domain sacsin protein is able to recruit Hsp70 chaperone action and has the potential to regulate the effects of other ataxia proteins" (Parfitt et al., PubMed: 19208651). A pseudogene associated with this gene is located on chromosome 11. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

SACS links:

LOC107984585 (HGNC:):

LOC107984585 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a chain Gamma-sarcoglycan (size 290) in uniprot entity SGCG_HUMAN there are 28 pathogenic changes around while only 1 benign (97%) in NM_000231.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 13-23320639-T-C is Pathogenic according to our data. Variant chr13-23320639-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 281085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23320639-T-C is described in Lovd as [Pathogenic]. Variant chr13-23320639-T-C is described in Lovd as [Pathogenic]. Variant chr13-23320639-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCG	NM_000231.3 linkuse as main transcript	c.581T>C	p.Leu194Ser	missense_variant, splice_region_variant	7/8	ENST00000218867.4	NP_000222.2	Q13326

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SGCG	ENST00000218867.4 linkuse as main transcript	c.581T>C	p.Leu194Ser	missense_variant, splice_region_variant	7/8	1	NM_000231.3	ENSP00000218867.3	Q13326
SACS	ENST00000682775.1 linkuse as main transcript	c.2186-8524A>G		intron_variant				ENSP00000508399.1	A0A804HLK7
SACS	ENST00000683210.1 linkuse as main transcript	c.2186-31396A>G		intron_variant				ENSP00000506739.1	A0A804HHS6
SACS	ENST00000684325.1 linkuse as main transcript	n.*104+927A>G		intron_variant				ENSP00000508121.1	A0A804HKY6

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

149822

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000296

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000198

AC:

AN:

201962

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

108042

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000470

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000254

AC:

AN:

1379876

Hom.:

Cov.:

AF XY:

0.0000277

AC XY:

AN XY:

685260

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000295

Gnomad4 OTH exome

AF:

0.0000702

GnomAD4 genome

AF:

0.0000133

AC:

AN:

149822

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73008

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000296

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000147

Hom.:

ExAC

AF:

0.0000332

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2C

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 01, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 03, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 194 of the SGCG protein (p.Leu194Ser). This variant is present in population databases (rs547818652, gnomAD 0.004%). This missense change has been observed in individuals with limb girdle muscular dystrophy (LGMD) (PMID: 9673983, 19770540). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Leu193Ser. ClinVar contains an entry for this variant (Variation ID: 281085). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SGCG function (PMID: 22095924). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 04, 2024	- -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 08, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 23, 2016	- -

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

May 04, 2022

Variant summary: SGCG c.581T>C (p.Leu194Ser) 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 2e-05 in 201962 control chromosomes. c.581T>C has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. 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 and showed that this variant disturbs the membrane localization of the protein. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

SGCG-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2024

The SGCG c.581T>C variant is predicted to result in the amino acid substitution p.Leu194Ser. This variant has been reported in the compound heterozygous and homozygous state in individuals with limb girdle muscular dystrophy (van der Kooi et al. 1998. PubMed ID: 9673983; Ginjaar et al. 2000. PubMed ID: 10993494; Khadilkar et al. 2009. PubMed ID: 19770540; Soheili et al. 2012. PubMed ID: 22095924; Supp. Table 1 in Ten Dam et al. 2019. PubMed ID: 30919934). Functional studies indicate this variant disrupts normal cell membrane localization (Soheili et al. 2012. PubMed ID: 22095924). This variant is reported in 0.0050% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.54

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.2

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MVP

1.0

MPC

0.48

ClinPred

0.98

GERP RS

5.6

Varity_R

0.84

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

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