Submissions for variant NM_005609.4(PYGM):c.425-26A>G

gnomAD frequency: 0.00009  dbSNP: rs764313717

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000454242	SCV000538059	likely pathogenic	Glycogen storage disease, type V	2015-12-04	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000454242	SCV000800559	uncertain significance	Glycogen storage disease, type V	2017-07-07	criteria provided, single submitter	clinical testing
GeneDx	RCV001564860	SCV001788091	likely pathogenic	not provided	2021-07-09	criteria provided, single submitter	clinical testing	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)
Revvity Omics, Revvity	RCV000454242	SCV002018993	likely pathogenic	Glycogen storage disease, type V	2023-05-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000454242	SCV002197748	pathogenic	Glycogen storage disease, type V	2024-01-25	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000454242	SCV002511722	likely pathogenic	Glycogen storage disease, type V	2022-04-25	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000454242	SCV004207212	likely pathogenic	Glycogen storage disease, type V	2024-03-23	criteria provided, single submitter	clinical testing
OMIM	RCV000002406	SCV000022564	pathogenic	McArdle disease, mild	2009-06-01	no assertion criteria provided	literature only