ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

BS1, PP3

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 634 of the PYGL protein (p.Asp634His). This variant is present in population databases (rs35026927, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with glycogen storage disease and/or PYGL-related disease (PMID: 17705025). ClinVar contains an entry for this variant (Variation ID: 21331). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PYGL protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The variant is observed in the gnomAD v2.1.1 ( https://gnomad.broadinstitute.org ) dataset at total allele frequency of 0.380%. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.45). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PYGL-related disorder with insufficient/conflicting evidence (PMID: 31768638 / ClinVar ID: VCV000021331). A different missense change at the same codon (p.Asp634Gly) has been reported to be associated with PYGL-related disorder (PMID: 31768638). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

PYGL: PP3, BS2

The PYGL c.1900G>C variant is predicted to result in the amino acid substitution p.Asp634His. This variant has been reported in individuals with Glycogen storage disease VI (Beauchamp et al. 2007. PubMed ID: 17705025; Aeppli et al 2019. PubMed ID: 31768638). It was also reported in the heterozygous state in two individuals with possible GSD type VI, however, no second PYGL variants were observed (Ghosh et al. 2017. PubMed ID: 28468868; Degrassi et al. 2021. PubMed ID: 32505569). This variant is reported in 0.65% of alleles in individuals of European (Non-Finnish) descent including two homozygotes in gnomAD. and while this relatively high minor allele frequency argues against pathogenicity, we have observed the c.1900G>C variant in the heterozygous state in more than twenty symptomatic patients at PreventionGenetics (Internal Data). In at least ten of these patients, we found a second potential causative variant in PYGL. Family testing for several of these patients suggests that the variants followed expected Mendelian inheritance patterns for a recessive disorder. While we suspect this variant may possibly be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.

Variant interpreted as Uncertain significance and reported on 12-21-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.