14-50911799-C-G
Variant names:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3BP4_ModerateBS1BS2
The NM_002863.5(PYGL):āc.1900G>Cā(p.Asp634His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,614,102 control chromosomes in the GnomAD database, including 49 homozygotes. 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: š 0.0042 ( 2 hom., cov: 32)
Exomes š: 0.0069 ( 47 hom. )
Consequence
PYGL
NM_002863.5 missense
NM_002863.5 missense
Scores
15
2
2
Clinical Significance
Conservation
PhyloP100: 7.88
Genes affected
PYGL (HGNC:9725): (glycogen phosphorylase L) This gene encodes a homodimeric protein that catalyses the cleavage of alpha-1,4-glucosidic bonds to release glucose-1-phosphate from liver glycogen stores. This protein switches from inactive phosphorylase B to active phosphorylase A by phosphorylation of serine residue 15. Activity of this enzyme is further regulated by multiple allosteric effectors and hormonal controls. Humans have three glycogen phosphorylase genes that encode distinct isozymes that are primarily expressed in liver, brain and muscle, respectively. The liver isozyme serves the glycemic demands of the body in general while the brain and muscle isozymes supply just those tissues. In glycogen storage disease type VI, also known as Hers disease, mutations in liver glycogen phosphorylase inhibit the conversion of glycogen to glucose and results in moderate hypoglycemia, mild ketosis, growth retardation and hepatomegaly. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Feb 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
PP3
Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.08306286).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00425 (647/152322) while in subpopulation NFE AF= 0.00744 (506/68022). AF 95% confidence interval is 0.0069. There are 2 homozygotes in gnomad4. There are 264 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AR gene
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PYGL | ENST00000216392.8 | c.1900G>C | p.Asp634His | missense_variant | Exon 16 of 20 | 1 | NM_002863.5 | ENSP00000216392.7 | ||
PYGL | ENST00000532462.5 | c.1900G>C | p.Asp634His | missense_variant | Exon 16 of 20 | 1 | ENSP00000431657.1 | |||
PYGL | ENST00000544180.6 | c.1798G>C | p.Asp600His | missense_variant | Exon 15 of 19 | 2 | ENSP00000443787.1 | |||
PYGL | ENST00000532107.2 | n.73G>C | non_coding_transcript_exon_variant | Exon 1 of 4 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00425 AC: 647AN: 152204Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.00373 AC: 939AN: 251436Hom.: 2 AF XY: 0.00356 AC XY: 484AN XY: 135876
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GnomAD4 exome AF: 0.00687 AC: 10040AN: 1461780Hom.: 47 Cov.: 31 AF XY: 0.00668 AC XY: 4858AN XY: 727196
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GnomAD4 genome AF: 0.00425 AC: 647AN: 152322Hom.: 2 Cov.: 32 AF XY: 0.00354 AC XY: 264AN XY: 74490
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:2Other:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Glycogen storage disease, type VI Uncertain:5Benign:1Other:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | 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. - |
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | 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. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 20, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 27, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | Sep 01, 2022 | 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. - |
not provided Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | PYGL: PP3, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 03, 2022 | BS1, PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 13, 2017 | - - |
PYGL-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 20, 2024 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;.;D
Vest4
MVP
MPC
0.59
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at