ClinVar Miner

Submissions for variant NM_002863.5(PYGL):c.1620+1G>A

gnomAD frequency: 0.00006  dbSNP: rs113993981
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000012776 SCV000915645 likely pathogenic Glycogen storage disease, type VI 2018-08-17 criteria provided, single submitter clinical testing The PYGL c.1620+1G>A variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.1620+1G>A variant, also described as IVS13+1G>A, is a reported founder variant in the Mennonite population, and has been reported in one study in which it was found in a homozygous state in five individuals with glycogen storage disease type VI (GSD VI) from a large, interrelated Mennonite family (Chang et al. 1998). The parents of all affected individuals were confirmed to be heterozygous carriers. The variant was absent from 52 healthy, unrelated controls but is reported at a frequency of 0.000060 in the European (non-Finnish) population of the Exome Aggregation Consortium. RT-PCR analysis on samples from the affected individuals revealed that the c.1620+1G>A variant causes aberrant splicing, creating two abnormal cDNA products including one that utilizes a cryptic donor site that yields a product missing the last three residues of exon 13 and another lacking all of exon 13 (Chang et al. 1998). Based on the evidence and potential impact of splice acceptor variants, the c.1620+1G>A variant is classified as likely pathogenic for glycogen storage disease type VI. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp RCV000012776 SCV005837173 pathogenic Glycogen storage disease, type VI 2025-01-17 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 13 of the PYGL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PYGL are known to be pathogenic (PMID: 9536091, 21646031). This variant is present in population databases (rs113993981, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with glycogen storage disease type VI (PMID: 9536091, 21646031). ClinVar contains an entry for this variant (Variation ID: 11996). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012776 SCV000033015 pathogenic Glycogen storage disease, type VI 1998-05-01 no assertion criteria provided literature only
GeneReviews RCV000012776 SCV000040943 not provided Glycogen storage disease, type VI no assertion provided literature only

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