14-50911799-C-G

Position:

• chr14-50911799-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3 BP4_Moderate BS1 BS2

The ENST00000216392.8(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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D634E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (47 hom.)
• Consequence: PYGL ENST00000216392.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2 O:2
• 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]

PYGL (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
PYGL	NM_002863.5	c.1900G>C	p.Asp634His	missense_variant	16/20	ENST00000216392.8	NP_002854.3
PYGL	NM_001163940.2	c.1798G>C	p.Asp600His	missense_variant	15/19		NP_001157412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGL	ENST00000216392.8	c.1900G>C	p.Asp634His	missense_variant	16/20	1	NM_002863.5	ENSP00000216392.7
PYGL	ENST00000532462.5	c.1900G>C	p.Asp634His	missense_variant	16/20	1		ENSP00000431657.1
PYGL	ENST00000544180.6	c.1798G>C	p.Asp600His	missense_variant	15/19	2		ENSP00000443787.1
PYGL	ENST00000532107.2	n.73G>C		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.00425 AC: 647 AN: 152204 Hom.: 2 Cov.: 32

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.: 2 AF XY: 0.00356 AC XY: 484 AN XY: 135876

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.: 47 Cov.: 31 AF XY: 0.00668 AC XY: 4858 AN XY: 727196

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.: 2 Cov.: 32 AF XY: 0.00354 AC XY: 264 AN XY: 74490

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.: 4

Bravo AF: 0.00383

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00351 AC: 426

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00687

EpiControl AF: 0.00605

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:2 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease, type VI Uncertain:5 Benign:1 Other:2

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	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	literature only	GeneReviews	-	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 27, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	3billion	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Uncertain:2 Benign: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.083	T;T;T
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.0	.;.;H
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.72	T
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	T
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

Other links and lift over

dbSNP: rs35026927; hg19: chr14-51378517; COSMIC: COSV53585973; COSMIC: COSV53585973;