GeneBe

rs773204705

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PP2PP3_StrongPP5

The NM_005609.4(PYGM):​c.1193C>T​(p.Pro398Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000815 in 1,594,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P398P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

PYGM
NM_005609.4 missense

Scores

16
2
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:3

Conservation

PhyloP100: 10.0

Publications

2 publications found
Variant links:
Genes affected
PYGM (HGNC:9726): (glycogen phosphorylase, muscle associated) This gene encodes a muscle enzyme involved in glycogenolysis. Highly similar enzymes encoded by different genes are found in liver and brain. Mutations in this gene are associated with McArdle disease (myophosphorylase deficiency), a glycogen storage disease of muscle. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Sep 2009]
PYGM Gene-Disease associations (from GenCC):
  • glycogen storage disease V
    Inheritance: AR, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_005609.4
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 37 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 0.046884 (below the threshold of 3.09). Trascript score misZ: 1.6804 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease V.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.974
PP5
Variant 11-64753925-G-A is Pathogenic according to our data. Variant chr11-64753925-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 552430.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PYGMNM_005609.4 linkc.1193C>T p.Pro398Leu missense_variant Exon 10 of 20 ENST00000164139.4 NP_005600.1 P11217-1
PYGMNM_001164716.1 linkc.929C>T p.Pro310Leu missense_variant Exon 8 of 18 NP_001158188.1 P11217-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PYGMENST00000164139.4 linkc.1193C>T p.Pro398Leu missense_variant Exon 10 of 20 1 NM_005609.4 ENSP00000164139.3 P11217-1
PYGMENST00000377432.7 linkc.929C>T p.Pro310Leu missense_variant Exon 8 of 18 2 ENSP00000366650.3 P11217-2
PYGMENST00000460413.1 linkn.270C>T non_coding_transcript_exon_variant Exon 2 of 3 3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152170
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000919
AC:
2
AN:
217694
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000636
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000832
AC:
12
AN:
1442492
Hom.:
0
Cov.:
37
AF XY:
0.00000838
AC XY:
6
AN XY:
715724
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33120
American (AMR)
AF:
0.0000474
AC:
2
AN:
42164
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25748
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38878
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83324
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51514
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5732
European-Non Finnish (NFE)
AF:
0.00000816
AC:
9
AN:
1102364
Other (OTH)
AF:
0.0000168
AC:
1
AN:
59648
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.513
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152170
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74348
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000241
AC:
1
AN:
41428
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68016
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000409
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.00000827
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Glycogen storage disease, type V Pathogenic:3Uncertain:3
Jan 22, 2020
Natera, Inc.
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Oct 05, 2020
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 17, 2024
Baylor Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 398 of the PYGM protein (p.Pro398Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with glycogen storage disease (PMID: 21880526; Invitae). ClinVar contains an entry for this variant (Variation ID: 552430). 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 PYGM protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jun 09, 2017
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 10, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.89
.;D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.6
.;H
PhyloP100
10
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-8.5
D;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
.;D
Vest4
0.95
MutPred
0.86
.;Gain of helix (P = 0.0854);
MVP
1.0
MPC
0.85
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.96
gMVP
0.89
Mutation Taster
=10/90
disease causing

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

Other links and lift over

dbSNP: rs773204705; hg19: chr11-64521397; COSMIC: COSV51220162; COSMIC: COSV51220162; API