rs764313717
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_005609.4(PYGM):c.425-26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,612,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
PYGM
NM_005609.4 intron
NM_005609.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0760
Genes affected
PYGM (HGNC:9726): (glycogen phosphorylase, muscle associated) This gene encodes a muscle enzyme involved in glycogenolysis. Highly similar enzymes encoded by different genes are found in liver and brain. Mutations in this gene are associated with McArdle disease (myophosphorylase deficiency), a glycogen storage disease of muscle. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 11-64758375-T-C is Pathogenic according to our data. Variant chr11-64758375-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2316.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Pathogenic=1, Uncertain_significance=1}. Variant chr11-64758375-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PYGM | NM_005609.4 | c.425-26A>G | intron_variant | ENST00000164139.4 | |||
PYGM | NM_001164716.1 | c.244-109A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PYGM | ENST00000164139.4 | c.425-26A>G | intron_variant | 1 | NM_005609.4 | P1 | |||
PYGM | ENST00000377432.7 | c.244-109A>G | intron_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000921 AC: 14AN: 152038Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000558 AC: 14AN: 250854Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135654
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GnomAD4 exome AF: 0.000125 AC: 183AN: 1460640Hom.: 0 Cov.: 34 AF XY: 0.000113 AC XY: 82AN XY: 726656
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:7Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Glycogen storage disease, type V Pathogenic:5Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 07, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Dec 04, 2015 | The c.425-26A>G intron variant in the PYGM gene has been previously reported in one affected individual with autosomal recessive McArdle disease who harbored this variant in trans with a second common pathogenic missense variant (G205S). This variant has been shown to result in atypical mild phenotype (Vissing et al., 2009). Splicing studies show this c.425-26A>G variant causes exon skipping of exon 4 in the PYGM gene (Vissing et al., 2009). The c.425-26A>G variant is present at low frequencies (ExAC = 0.006%) or absent in the control population databases (Exome Sequencing Project [ESP] and 1000 Genomes). PYGM is the only gene in which mutations are known to cause McArdle disease. Therefore, this collective evidence supports the classification of the c.425-26A>G as a recessive likely pathogenic variant for McArdle disease. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 17, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 25, 2022 | Variant summary: PYGM c.425-26A>G alters a non-conserved nucleotide located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, at least one publication reports experimental evidence that this variant affects mRNA splicing resulting in skipping of exon 4 (Vissing_2009). The variant allele was found at a frequency of 5.6e-05 in 250854 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PYGM causing Glycogen Storage Disease, Type V (5.6e-05 vs 0.0035), allowing no conclusion about variant significance. c.425-26A>G has been reported in the literature as a compound heterozygous genotype in individuals affected with Glycogen Storage Disease, Type V (example, Vissing_2009, Gandhi_2021, Pizzamiglio_2021). These data indicate that the variant may be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely Pathogenic/Pathogenic, n=4; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change falls in intron 3 of the PYGM gene. It does not directly change the encoded amino acid sequence of the PYGM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs764313717, gnomAD 0.01%). This variant has been observed in individual(s) with glycogen storage disease (PMID: 19433441). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2316). Studies have shown that this variant results in skipping of exon 4 and introduces a premature termination codon (PMID: 19433441). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 20, 2023 | - - |
McArdle disease, mild Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2009 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 09, 2021 | Canonical splice site variant predicted to result in the skipping of exon 4, however trace amounts of the aberrantly spliced product and residual PYGM activity suggest that the c.425-26A variant is "leaky", allowing some normal spliced product to be generated (Vissing et al., 2009); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 34215481, 19433441, 32075227, 27535533, 25914343, 29754767) - |
Computational scores
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BayesDel_noAF
Benign
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Benign
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at