rs786204786
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000231.3(SGCG):c.525del(p.Phe175LeufsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L174L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000231.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SGCG | NM_000231.3 | c.525del | p.Phe175LeufsTer20 | frameshift_variant | 6/8 | ENST00000218867.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SGCG | ENST00000218867.4 | c.525del | p.Phe175LeufsTer20 | frameshift_variant | 6/8 | 1 | NM_000231.3 | P1 | |
SACS | ENST00000683210.1 | c.2186-6187del | intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152134Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251462Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135900
GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461662Hom.: 0 Cov.: 30 AF XY: 0.0000536 AC XY: 39AN XY: 727148
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6AN XY: 74440
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2C Pathogenic:13
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change creates a premature translational stop signal (p.Phe175Leufs*20) 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 present in population databases (rs765500509, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with limb girdle muscular dystrophy (PMID: 7481775, 12040521, 22240777, 23929688, 24552312). ClinVar contains an entry for this variant (Variation ID: 189243). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 22, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 15, 2014 | The Phe175LeufsX20 variant in SGCG has been reported in many individuals with limb girdle muscular dystrophy type 2C (LGMD2C; Noguchi 1995, Boyden 2010, Herson 2012, Schroder 2014, El Kerch 2014). Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 175 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Complete loss of SGCG function is an established disease mechanism in LGMD2C. In summary, this variant meets our criteria to be classified as pathogenic for LGMD2C in an autosomal recessive manner. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000189243 / PMID: 7481775). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Nov 30, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 30, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 08, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 12, 2000 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Feb 22, 2017 | - - |
Pathogenic, no assertion criteria provided | research | Section for Clinical Neurogenetics, University of Tübingen | Aug 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The homozygous p.Phe175LeufsTer20 variant in SGCG was identified by our study in five individuals (four siblings and one unrelated individual) with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.006092% (15/246240) of chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs765500509). Although this variant has been seen in the general population, the frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 175 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SGCG gene is an established disease mechanism in autosomal recessive LGMD. This variant has also been reported in ClinVar (Variation ID: 189243). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant and multiple reports in ClinVar. ACMG/AMP Criteria applied: PM2, PVS1, PP1 (Richards 2015). - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 19, 2014 | The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity. Found in multiple individuals with expected phenotype for this gene. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 26, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 29, 2021 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11693784, 18285821, 22367371, 17994539, 16832103, 23929688, 7481775, 16616845, 15954112, 14678800, 26404900, 25252238, 16916601, 22240777, 24552312, 12040521, 27759885, 30919934, 31130284, 31980526, 31127727, 8900232, 20623375, 19770540, 10942431, 32214227, 25214167, 32528171, 31589614) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at