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):c.1900G>C(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: 𝑓 0.0042 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0069 ( 47 hom. )

Consequence

PYGL
NM_002863.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:2O:2

Conservation

PhyloP100: 7.88

Variant links:

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]

PYGL links:

Genome browser will be placed here

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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGL	NM_002863.5 link	c.1900G>C	p.Asp634His	missense_variant	Exon 16 of 20	ENST00000216392.8	NP_002854.3	P06737-1
PYGL	NM_001163940.2 link	c.1798G>C	p.Asp600His	missense_variant	Exon 15 of 19		NP_001157412.1	P06737-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PYGL	ENST00000216392.8 link	c.1900G>C	p.Asp634His	missense_variant	Exon 16 of 20	1	NM_002863.5	ENSP00000216392.7	P06737-1
PYGL	ENST00000532462.5 link	c.1900G>C	p.Asp634His	missense_variant	Exon 16 of 20	1		ENSP00000431657.1	E9PK47
PYGL	ENST00000544180.6 link	c.1798G>C	p.Asp600His	missense_variant	Exon 15 of 19	2		ENSP00000443787.1	P06737-2
PYGL	ENST00000532107.2 link	n.73G>C		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.00425

AC:

647

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00744

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00373

AC:

939

AN:

251436

Hom.:

AF XY:

0.00356

AC XY:

484

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00576

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.00203

Gnomad NFE exome

AF:

0.00633

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00687

AC:

10040

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00668

AC XY:

4858

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00143

Gnomad4 ASJ exome

AF:

0.00662

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000858

Gnomad4 FIN exome

AF:

0.00215

Gnomad4 NFE exome

AF:

0.00829

Gnomad4 OTH exome

AF:

0.00603

GnomAD4 genome

AF:

0.00425

AC:

647

AN:

152322

Hom.:

Cov.:

AF XY:

0.00354

AC XY:

264

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00127

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00744

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00621

Hom.:

Bravo

AF:

0.00383

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.00351

AC:

426

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00687

EpiControl

AF:

0.00605

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

Jul 27, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

3billion, Medical Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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

Uncertain:2Benign:1

Mar 13, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 03, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, PP3 -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PYGL: PP3, BS2 -

PYGL-related disorder

Uncertain:1

Sep 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

.;.;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.60

MetaRNN

Benign

0.083

T;T;T

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.0

.;.;H

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.5

D;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.99

MVP

1.0

MPC

0.59

ClinPred

0.16

GERP RS

5.6

Varity_R

0.95

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over