rs780348174
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000231.3(SGCG):c.800_801del(p.Cys267SerfsTer51) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
SGCG
NM_000231.3 frameshift
NM_000231.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.07
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-23324457-CTG-C is Pathogenic according to our data. Variant chr13-23324457-CTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324457-CTG-C is described in Lovd as [Pathogenic]. Variant chr13-23324457-CTG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SGCG | NM_000231.3 | c.800_801del | p.Cys267SerfsTer51 | frameshift_variant | 8/8 | ENST00000218867.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SGCG | ENST00000218867.4 | c.800_801del | p.Cys267SerfsTer51 | frameshift_variant | 8/8 | 1 | NM_000231.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251472Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135916
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461806Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 727210
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2C Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 13, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 14, 2023 | ClinVar contains an entry for this variant (Variation ID: 552513). This variant is also known as ∆801–TC. This frameshift has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 8923014, 24638197). This variant is present in population databases (rs780348174, gnomAD 0.01%). This sequence change results in a frameshift in the SGCG gene (p.Cys267Serfs*51). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the SGCG protein and extend the protein by 25 additional amino acid residues. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys283 amino acid residue in SGCG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8968757, 22095924). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 09, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1996 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2020 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at