GeneBe

NM_005609.4:c.415C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_005609.4(PYGM):​c.415C>T​(p.Arg139Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,864 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).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

PYGM
NM_005609.4 missense

Scores

15
3
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:3

Conservation

PhyloP100: 4.03
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
Variant 11-64758446-G-A is Pathogenic according to our data. Variant chr11-64758446-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555716.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=3, Likely_pathogenic=1}. Variant chr11-64758446-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PYGMNM_005609.4 linkc.415C>T p.Arg139Trp missense_variant Exon 3 of 20 ENST00000164139.4 NP_005600.1 P11217-1
PYGMNM_001164716.1 linkc.244-180C>T intron_variant Intron 1 of 17 NP_001158188.1 P11217-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PYGMENST00000164139.4 linkc.415C>T p.Arg139Trp missense_variant Exon 3 of 20 1 NM_005609.4 ENSP00000164139.3 P11217-1
PYGMENST00000377432.7 linkc.244-180C>T intron_variant Intron 1 of 17 2 ENSP00000366650.3 P11217-2

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152092
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251172
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135778
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000466
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461654
Hom.:
0
Cov.:
34
AF XY:
0.00000688
AC XY:
5
AN XY:
727144
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152210
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74414
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000189
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Glycogen storage disease, type V Pathogenic:4Uncertain:3
Oct 25, 2023
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 28, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The PYGM c.415C>T (p.Arg139Trp) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg139Trp variant has been reported in two studies in which it is found a total of four individuals with glycogen storage disease type V, including three homozygotes (two of whom are siblings), and one compound heterozygote in trans with a known pathogenic variant (Martin et al. 2004; Deschauer et al. 2007). Control data are unavailable for this variant which is reported at a frequency of 0.000046 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Arg139Trp variant is classified as likely pathogenic for glycogen storage disease type V. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Mar 13, 2019
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 139 of the PYGM protein (p.Arg139Trp). This variant is present in population databases (rs367990192, gnomAD 0.006%). This missense change has been observed in individuals with McArdle disease (PMID: 14748827, 17404776, 34373715, 34534370). ClinVar contains an entry for this variant (Variation ID: 555716). 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%. For these reasons, this variant has been classified as Pathogenic. -

Jun 10, 2022
DASA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.415C>T;p.(Arg139Trp) missense change has been observed in affected individual(s)(PMID: 17404776; 32075227; 34534370; 34373715) - PS4. The variant is present at low allele frequencies population databases (rs367990192– gnomAD 0.0003287%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Arg139Trp) was detected in trans with a Pathogenic variant (PMID: 17404776; 32075227; 34534370; 34373715) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 34373715) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic -

Dec 28, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 05, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.89
D
Eigen
Pathogenic
0.78
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.6
H
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-7.0
D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.89
MutPred
0.95
Loss of methylation at R139 (P = 0.0124);
MVP
0.99
MPC
0.86
ClinPred
1.0
D
GERP RS
4.5
Varity_R
0.96
gMVP
0.94

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.

Other links and lift over

dbSNP: rs367990192; hg19: chr11-64525918; API