rs144081869

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_005609.4(PYGM):c.2056G>A(p.Gly686Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G686E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

PYGM
NM_005609.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.87

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_005609.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-64750496-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2847782.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

PP5

Variant 11-64750497-C-T is Pathogenic according to our data. Variant chr11-64750497-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64750497-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGM	NM_005609.4 linkuse as main transcript	c.2056G>A	p.Gly686Arg	missense_variant	17/20	ENST00000164139.4
PYGM	NM_001164716.1 linkuse as main transcript	c.1792G>A	p.Gly598Arg	missense_variant	15/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGM	ENST00000164139.4 linkuse as main transcript	c.2056G>A	p.Gly686Arg	missense_variant	17/20	1	NM_005609.4	P1	P11217-1
PYGM	ENST00000377432.7 linkuse as main transcript	c.1792G>A	p.Gly598Arg	missense_variant	15/18	2			P11217-2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152246

Hom.:

Cov.:

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251480

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135916

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:

0.0000924

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727242

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:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000555

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type V

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 686 of the PYGM protein (p.Gly686Arg). This variant is present in population databases (rs144081869, gnomAD 0.009%). This missense change has been observed in individual(s) with glycogen storage disease type V (PMID: 9506549, 17404776). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Gly685Arg. ClinVar contains an entry for this variant (Variation ID: 2306). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 31, 2023	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30560358, 9506549, 17404776, 25740218, 17217859, 29350794, 31179311, 32075227, 27303362, 34534370, 37091313) -

Tip-toe gait

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Apr 07, 2021

- -

PYGM-related condition

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2023

The PYGM c.2056G>A variant is predicted to result in the amino acid substitution p.Gly686Arg. This variant has been reported in the compound heterozygous state with a second causative PYGM variant in several patients with histochemically or biochemically confirmed GSD V (Vorgerd et al. 1998. PubMed ID: 9506549, referred to as p.Gly685Arg; Deschauer et al. 2007. PubMed ID: 17404776). An additional patient was identified via use of the non-ischemic forearm exercise test, and was then found to be compound heterozygous for the c.2056G>A and c.148C>T (described above) variants (Hogrel et al. 2015. PubMed ID: 25740218). We have also observed this variant at PreventionGenetics, in the homozygous or compound heterozygous state, in two patients with suspected GSD V (internal data). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-64517969-C-T). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.60

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.95

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-7.0

D;D

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

1.0

.;D

Vest4

1.0

MutPred

0.99

.;Gain of MoRF binding (P = 0.0256);

MVP

0.99

MPC

0.92

ClinPred

1.0

GERP RS

4.9

Varity_R

0.97

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over