rs727502871
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000345003.9(GYG1):c.487del(p.Asp163ThrfsTer5) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000409 in 1,610,984 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00042 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00041 ( 0 hom. )
Consequence
GYG1
ENST00000345003.9 frameshift, splice_region
ENST00000345003.9 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.60
Genes affected
GYG1 (HGNC:4699): (glycogenin 1) This gene encodes a member of the glycogenin family. Glycogenin is a glycosyltransferase that catalyzes the formation of a short glucose polymer from uridine diphosphate glucose in an autoglucosylation reaction. This reaction is followed by elongation and branching of the polymer, catalyzed by glycogen synthase and branching enzyme, to form glycogen. This gene is expressed in muscle and other tissues. Mutations in this gene result in glycogen storage disease XV. This gene has pseudogenes on chromosomes 1, 8 and 13 respectively. Alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Sep 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 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 3-149009277-TG-T is Pathogenic according to our data. Variant chr3-149009277-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 162665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-149009277-TG-T is described in Lovd as [Pathogenic]. Variant chr3-149009277-TG-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GYG1 | NM_004130.4 | c.487del | p.Asp163ThrfsTer5 | frameshift_variant, splice_region_variant | 5/8 | ENST00000345003.9 | NP_004121.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GYG1 | ENST00000345003.9 | c.487del | p.Asp163ThrfsTer5 | frameshift_variant, splice_region_variant | 5/8 | 1 | NM_004130.4 | ENSP00000340736 |
Frequencies
GnomAD3 genomes 0.000421 AC: 64AN: 152178Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000398 AC: 100AN: 251230Hom.: 0 AF XY: 0.000339 AC XY: 46AN XY: 135850
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GnomAD4 exome AF: 0.000408 AC: 595AN: 1458688Hom.: 0 Cov.: 30 AF XY: 0.000408 AC XY: 296AN XY: 725976
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GnomAD4 genome 0.000420 AC: 64AN: 152296Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28AN XY: 74478
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Glycogen storage disease XV Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Sep 27, 2022 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2010 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Sep 17, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 22, 2022 | - - |
Polyglucosan body myopathy type 2 Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 05, 2023 | Variant summary: GYG1 c.487delG (p.Asp163ThrfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar and associated with Polyglucosan Body Myopathy Type 2 in HGMD. The variant allele was found at a frequency of 0.0004 in 251230 control chromosomes. c.487delG has been reported in the literature in multiple homozygous or compound heterozygous individuals affected with Polyglucosan Body Myopathy Type 2 (example: Desikan_2018) or with phenotypes consistent with the disease (examples: Moslemi_2010, BenYaou_2017, Hedberg-Oldfors_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine 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 (n=9). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 25, 2023 | The heterozygous p.Asp163ThrfsTer5 variant in GYG1 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 162661), in one individual with congenital myopathy. This individual also carried a pathogenic variant (ClinVar Variation ID: 162661); however, the phase of these variants is unknown at this time. The p.Asp163ThrfsTer5 variant has been previously reported in six unrelated individuals with polyglucosan body myopathy type 2 (PMID: 29422440, PMID: 29143313, PMID: 29264399, PMID: 28453664, PMID: 25272951, PMID: 20357282), but has been identified in 95/129080 (0.07360%) of non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1451817453). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 162665) and has been interpreted as pathogenic by the NIH Undiagnosed Diseases Network, GeneDx, Invitae, CeGaT Center for Human Genetics Tuebingen, Eurofins NTD LLC (GA), Mass General Brigham Personalized Medicine Laboratory for Molecular Medicine, OMIM, and PerkinElmer Genomics. Of these six affected unrelated individuals that were previously reported, four were homozygotes (PMID: 29422440, PMID: 29264399, PMID: 28453664, PMID: 25272951) and one was compound heterozygote who carried a variant of uncertain significance in trans (PMID: 20357282), which increases the likelihood that the p.Asp163ThrfsTer5 variant is pathogenic. RT-PCR analysis performed on RNA from patient tissue shows undetectable expression (PMID: 29143313, PMID: 20357282, PMID: 25272951), supporting nonsense-mediated decay of the transcript. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 163 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GYG1 gene is an established disease mechanism in autosomal recessive polyglucosan body myopathy type 2. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive polyglucosan body myopathy type 2. ACMG/AMP Criteria applied: PVS1, PS3_Moderate, PM3 (Richards 2015). - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 12, 2018 | The p.Asp163ThrfsX5 variant in GYG1 has been reported in 2 homozygous and 2 comp ound heterozygous individuals with clinical features of polyglucosan body myopat hy 2 and segregated in the compound heterozygous state in 1 affected relative ( Ben Yaou 2017, Hedberg-Oldfors 2018, Krag 2017, Moslemi 2010). This variant has been identified in 0.076% (96/126642) of European chromosomes by the Genome Aggr egation Database (gnomAD, http://gnmad.broadinstitute.org) and reported in ClinV ar (Variation ID#162665). Although this variant has been seen in the general po pulation, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the pro tein?s amino acid sequence beginning at position 163 and leads to a premature te rmination codon 5 amino acids downstream. This alteration is then predicted to l ead to a truncated or absent protein. Biallelic loss of function of the GYG1 gen e is strongly associated with polyglucosan body myopathy 2. In summary, this var iant meets criteria to be classified as pathogenic for polyglucosan body myopath y 2 in an autosomal recessive manner based upon probands, segregation, and pred icted impact on protein. ACMG/AMP Criteria applied: PVS1_Strong, PM3, PP1. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2022 | 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; This variant is associated with the following publications: (PMID: 28453664, 29143313, 29264399, 20357282, 25272951, 29142088, 31628455, 34426522, 31589614, 31980526, 32528171, 29422440) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 16, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | GYG1: PM3:Very Strong, PVS1, PM2 - |
Glycogen storage disease XV;C4015452:Polyglucosan body myopathy type 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change creates a premature translational stop signal (p.Asp163Thrfs*5) in the GYG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GYG1 are known to be pathogenic (PMID: 20357282, 25272951). This variant is present in population databases (rs764622581, gnomAD 0.08%). This premature translational stop signal has been observed in individuals with glycogen storage disease type XV (PMID: 20357282, 29264399, 29422440). This variant is also known as c.484delG. ClinVar contains an entry for this variant (Variation ID: 162665). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at