13-23320639-T-G

Variant names:

• chr13-23320639-T-G
• rs547818652
• NM_000231.3:c.581T>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000231.3(SGCG):​c.581T>G​(p.Leu194*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000362 in 1,379,876 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: SGCG NM_000231.3 stop_gained, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.86
• Publications: 0 publications found

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]

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 Gene-Disease associations (from GenCC):

• Charlevoix-Saguenay spastic ataxia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

LOC107984585 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-23320639-T-G is Pathogenic according to our data. Variant chr13-23320639-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1691313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCG	NM_000231.3	c.581T>G	p.Leu194*	stop_gained, splice_region_variant	Exon 7 of 8	ENST00000218867.4	NP_000222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCG	ENST00000218867.4	c.581T>G	p.Leu194*	stop_gained, splice_region_variant	Exon 7 of 8	1	NM_000231.3	ENSP00000218867.3
SACS	ENST00000682775.1	c.2186-8524A>C		intron_variant	Intron 9 of 9			ENSP00000508399.1
SACS	ENST00000683210.1	c.2186-31396A>C		intron_variant	Intron 9 of 9			ENSP00000506739.1
SACS	ENST00000684325.1	n.*104+927A>C		intron_variant	Intron 10 of 10			ENSP00000508121.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000362 AC: 5 AN: 1379876 Hom.: 0 Cov.: 32 AF XY: 0.00000584 AC XY: 4 AN XY: 685260

African (AFR) AF: 0.00 AC: 0 AN: 31922

American (AMR) AF: 0.00 AC: 0 AN: 38974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24616

East Asian (EAS) AF: 0.00 AC: 0 AN: 38332

South Asian (SAS) AF: 0.0000611 AC: 5 AN: 81858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5466

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1051412

Other (OTH) AF: 0.00 AC: 0 AN: 57020

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2C Pathogenic:2

Feb 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu194*) in the SGCG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SGCG are known to be pathogenic (PMID: 18285821). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (PMID: 28687063). ClinVar contains an entry for this variant (Variation ID: 1691313). For these reasons, this variant has been classified as Pathogenic.

May 18, 2022

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.581T>G variant is not present in publicly available population databases like 1000 Genomes, EVS, ExAC, gnomAD and Indian Exome Database. The variant is not present in our in-house exome database. The variant was not previously reported to ClinVar, HGMD and/or OMIM databases in any affected individuals. In-silico pathogenicity prediction programs like MutationTaster2, CADD, Varsome, InterVar etc. predicted this variant to be likely deleterious. A missense variant in the same position (c.581T>C, p.Leu194Ser) was earlier observed in patients affected with limb-girdle muscular dystrophy (PMID: 9673983, 19770540, 22095924) and reported to ClinVar (Accession: VCV000281085.15) and HGMD (ID: CM011483) as pathogenic/likely pathogenic. The c.581T>C variant has been reported to affect SGCG protein function (PMID: 22095924).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	38
DANN	Uncertain	0.97
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		6.9
Vest4		0.98
GERP RS		5.6
Mutation Taster		=3/197	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs547818652; hg19: chr13-23894778;