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

dbSNP: rs113993981

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Human Genetics	RCV001293797	SCV001482501	pathogenic	Glycogen storage disease, type VI	2020-08-27	criteria provided, single submitter	clinical testing	disease causing
Revvity Omics, Revvity	RCV001293797	SCV002019572	pathogenic	Glycogen storage disease, type VI	2023-09-11	criteria provided, single submitter	clinical testing
Suma Genomics	RCV001293797	SCV003762230	pathogenic	Glycogen storage disease, type VI		criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001293797	SCV004171846	pathogenic	Glycogen storage disease, type VI		criteria provided, single submitter	clinical testing	The invariant splice donor c.1620+1G>C in PYGL gene has been previously reported in homozygous and compound heterozygous state in multiple individuals affected with Glycogen storage disease (Kumar TV et al. 2022; Davit-Spraul A et al. 2011). The c.1620+1G>C variant is present with allele frequency of 0.0008% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple individuals). SpliceAI predicts this variant to cause splice donor loss (score-1). Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV001293797	SCV005874344	pathogenic	Glycogen storage disease, type VI		criteria provided, single submitter	research	A known canonical splice-site variant, g.50913028 C>G (NM_002863.5: c.1620+1 G>C) in intron 13 of PYGL was observed in homozygous state in the proband (Davit-Spraul et al., 2011; Kumar et al., 2022). Sanger validation and segregation analysis showed that this variant is present in homozygous state in the proband and heterozygous state in his parents. This variant is present in five individuals in heterozygous state and absent in homozygous state in gnomAD population database (v4.1.0). This variant is present in four individuals in heterozygous state and absent in homozygous state in our in-house database of 3518 exomes. This variant is reported in ClinVar database as pathogenic by four submitters (Accession: VCV000998110.12). This canonical splice-site variant is likely to result in aberrant splicing which may lead to either the formation of a truncated protein product or the transcript to undergo nonsense mediated mRNA decay.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293797	SCV005884205	pathogenic	Glycogen storage disease, type VI	2024-12-27	criteria provided, single submitter	clinical testing	Variant summary: PYGL c.1620+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of PYGL function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251208 control chromosomes. c.1620+1G>C has been reported in the literature in multiple homozygous or compound heterozygous individuals affected with Glycogen storage disease, type VI (e.g. Davit-Spraul_2011, Kumar_2022). 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. The following publications have been ascertained in the context of this evaluation (PMID: 21646031, 35834487). ClinVar contains an entry for this variant (Variation ID: 998110). Based on the evidence outlined above, the variant was classified as pathogenic.