rs113993979
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_002863.5(PYGL):c.1366G>A(p.Val456Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,614,130 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 1 hom. )
Consequence
PYGL
NM_002863.5 missense
NM_002863.5 missense
Scores
14
2
1
Clinical Significance
Conservation
PhyloP100: 7.91
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 Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.915
PP5
?
Variant 14-50915373-C-T is Pathogenic according to our data. Variant chr14-50915373-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 21328.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-50915373-C-T is described in Lovd as [Pathogenic]. Variant chr14-50915373-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PYGL | NM_002863.5 | c.1366G>A | p.Val456Met | missense_variant | 11/20 | ENST00000216392.8 | |
PYGL | NM_001163940.2 | c.1264G>A | p.Val422Met | missense_variant | 10/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PYGL | ENST00000216392.8 | c.1366G>A | p.Val456Met | missense_variant | 11/20 | 1 | NM_002863.5 | P1 | |
PYGL | ENST00000532462.5 | c.1366G>A | p.Val456Met | missense_variant | 11/20 | 1 | |||
PYGL | ENST00000544180.6 | c.1264G>A | p.Val422Met | missense_variant | 10/19 | 2 | |||
PYGL | ENST00000528757.2 | n.243G>A | non_coding_transcript_exon_variant | 2/2 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152118Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251482Hom.: 1 AF XY: 0.0000515 AC XY: 7AN XY: 135918
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461894Hom.: 1 Cov.: 32 AF XY: 0.0000316 AC XY: 23AN XY: 727248
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GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74426
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Glycogen storage disease, type VI Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 22, 2022 | For these reasons, this variant has been classified as Pathogenic. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 456 of the PYGL protein (p.Val456Met). This variant is present in population databases (rs113993979, gnomAD 0.01%). This missense change has been observed in individual(s) with glycogen storage disease type VI (PMID: 17705025, 21646031, 32892177). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21328). 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 expected to disrupt PYGL protein function. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;.;D
Vest4
MVP
MPC
0.53
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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