rs756251887

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.1349C>T(p.Ser450Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,604,590 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. S450S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PYGM
NM_005609.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.97

Publications

3 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

PYGM links:

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 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, 0.987

PP5

Variant 11-64753573-G-A is Pathogenic according to our data. Variant chr11-64753573-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283418.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGM	NM_005609.4 link	c.1349C>T	p.Ser450Leu	missense_variant	Exon 11 of 20	ENST00000164139.4	NP_005600.1	P11217-1
PYGM	NM_001164716.1 link	c.1085C>T	p.Ser362Leu	missense_variant	Exon 9 of 18		NP_001158188.1	P11217-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PYGM	ENST00000164139.4 link	c.1349C>T	p.Ser450Leu	missense_variant	Exon 11 of 20	1	NM_005609.4	ENSP00000164139.3	P11217-1
PYGM	ENST00000377432.7 link	c.1085C>T	p.Ser362Leu	missense_variant	Exon 9 of 18	2		ENSP00000366650.3	P11217-2
PYGM	ENST00000460413.1 link	n.*98C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000305

AC:

AN:

229518

AF XY:

0.0000318

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000895

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000294

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1452416

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

722260

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.0000906

AC:

AN:

44128

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25976

East Asian (EAS)

AF:

0.00

AC:

AN:

39486

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85310

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1109954

Other (OTH)

AF:

0.00

AC:

AN:

60072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41424

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000203

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000331

AC:

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:1

Feb 12, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 28, 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. -

Mar 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 450 of the PYGM protein (p.Ser450Leu). This variant is present in population databases (rs756251887, gnomAD 0.01%). This missense change has been observed in individual(s) with McArdle disease (PMID: 17404776). ClinVar contains an entry for this variant (Variation ID: 283418). 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. -

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

May 30, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PYGM c.1349C>T (p.Ser450Leu) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 3e-05 in 229718 control chromosomes. c.1349C>T has been reported in the literature in two individuals affected with McArdle disease, including one homozygote (Deschauer_2007). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 283418). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:1

Sep 16, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

.;D

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.5

.;H

PhyloP100

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.1

D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.81

.;P

Vest4

0.96

MutPred

0.95

.;Loss of glycosylation at S450 (P = 0.1061);

MVP

0.99

MPC

0.43

ClinPred

1.0

GERP RS

5.0

Varity_R

0.98

gMVP

0.97

Mutation Taster

=8/92

disease causing

(source)

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

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rs756251887

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over