11-64752486-T-C

Position:

• chr11-64752486-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_005609.4(PYGM):​c.1537A>G​(p.Ile513Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,614,136 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. I513I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (6 hom.)
• Consequence: PYGM NM_005609.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:6 O:1
• Conservation: PhyloP100: 2.72

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010278106).
• BS2: High Homozygotes in GnomAdExome4 at 6 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGM	NM_005609.4	c.1537A>G	p.Ile513Val	missense_variant	13/20	ENST00000164139.4
PYGM	NM_001164716.1	c.1273A>G	p.Ile425Val	missense_variant	11/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGM	ENST00000164139.4	c.1537A>G	p.Ile513Val	missense_variant	13/20	1	NM_005609.4	P1
PYGM	ENST00000377432.7	c.1273A>G	p.Ile425Val	missense_variant	11/18	2

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 358 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00537

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00350

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00302 AC: 758 AN: 251172 Hom.: 2 AF XY: 0.00303 AC XY: 411 AN XY: 135816

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.00671

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00296 AC: 4325 AN: 1461794 Hom.: 6 Cov.: 32 AF XY: 0.00310 AC XY: 2253 AN XY: 727190

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00240

Gnomad4 FIN exome AF: 0.00766

Gnomad4 NFE exome AF: 0.00307

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00235 AC: 358 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00227 AC XY: 169 AN XY: 74498

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00537

Gnomad4 NFE AF: 0.00350

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00284 Hom.: 1

Bravo AF: 0.00210

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00281 AC: 341

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00373

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease, type V Uncertain:1 Benign:3 Other:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 18, 2022	This sequence change replaces isoleucine with valine at codon 513 of the PYGM protein (p.Ile513Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs139570786, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with McArdle disease (PMID: 23653251; Invitae). ClinVar contains an entry for this variant (Variation ID: 194233). 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 not expected to disrupt PYGM protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	PYGM: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	This variant is associated with the following publications: (PMID: 26907767, 32420686, 24503134, 23653251, 25741863, 25214167, 30560358) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 21, 2023	- -

Tip-toe gait Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

May 31, 2021

Toe Walking has various causes, ranging from idiopathic or habitual reasons to an underlying neuromuscular disease. The most observed form of toe walking is idiopathic toe walking (ITW) - a diagnosis of exclusion. ITW occurs in about 5% of children after their second birthday and is a common problem in pediatric orthopedics. In about 70% of these cases, there is spontaneous remission within six months of the onset of ITW. If the toe walk persists, one can assume the presence of a non-idiopathic form of toe walk (n-ITW). In n-ITW, the causes of the abnormal gait are neurological or myogenic. Differential diagnoses such as infantile cerebral palsy, muscular dystrophy, spinal amyotrophy and hereditary motor-sensory neuropathy as well as rare metabolic disorders of the musculature must be considered (Pomarino et al., 2018). In our clinical ITW consultation, we screen children with n-ITW for a genetic form of tiptoe gait using next generation sequencing for gene variants in 49 genes. These are genes in which gene variants can lead to neuromuscular diseases in which an association with toe-tapping gait has been reported or can be suspected due to patients’ clinical symptoms. To the best of our knowledge, this is the first study in which several patients with toe walking displayed heterozygosity for pathogenic or likely pathogenic PYGM mutations and mild symptoms of the metabolic muscle disease McArdle. The findings of our research are in line with recently published observations in heterozygous family members patients with McArdle disease. We should mention that some of the patients in our cohort harbored heterozygous variants in other genes of our gene panel. However, the numbers in this study were too small to workout any resulting combined genetic effects. It is concluded that genetic conditions can contribute to the development of toe walking. Apparently, even a slight genetic weakening of the muscles can lead to changes to the gait pattern. Future studies must show how the pathomechanism can be explained for the PYGM variants and whether there are new therapeutic approaches to be developed based on this research. -

PYGM-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 25, 2022

The PYGM c.1537A>G variant is predicted to result in the amino acid substitution p.Ile513Val. This variant has been previously detected, in the heterozygous state with one other known pathogenic PYGM variant, in at least two unrelated patients with glycogen storage disease type V (GSD V, also known as McArdle Disease) (Gurgel-Giannetti et al. 2013. PubMed ID: 23653251; Savarese et al. 2014. PubMed ID: 25214167). In the patient reported by Gurgel-Giannetti et al., it was confirmed to be in trans with a known pathogenic variant. However, this variant is also reported at a minor allele frequency ranging from 0.12% to 0.65% in multiple populations in gnomAD, which may indicate this variant is too common to be a primary cause of disease (http://gnomad.broadinstitute.org/variant/11-64519958-T-C). This variant is reported with interpretations ranging from benign to uncertain in the ClinVar database (https://preview.ncbi.nlm.nih.gov/clinvar/variation/194233/). We have observed this variant internally in several patients, generally without a second plausible causative variant in PYGM. In summary, although we suspect that this variant may possibly be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Aug 09, 2023

Variant summary: PYGM c.1537A>G (p.Ile513Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 251172 control chromosomes, predominantly at a frequency of 0.0037 within the Non-Finnish European subpopulation, and is found in 2 homozygotes in the gnomAD database. The observed variant frequency in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in PYGM causing Glycogen Storage Disease, Type V phenotype (0.0035), suggesting that the variant may be a benign polymorphism. c.1537A>G has been reported in the literature as a compound heterozygous genotype in at least three individuals affected with Glycogen Storage Disease, Type V (e.g. Gurgel-Giannetti_2013, Zare_2022); however, two of these individuals were siblings who also had the variant in cis with a variant of uncertain significance (Zare_2022). The variant was also reported in the compound heterozygous state following multigene panel testing in an individual with limb-girdle muscular dystrophy who had a clinical diagnosis with histology showing dystrophic features (Savarese_2014). These reports do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type V. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23653251, 25214167, PMCID: PMC9627962). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: benign/likely benign (n=5), VUS (n=3), likely patogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Benign	0.80
DEOGEN2	Benign	0.27	.;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.0050	.;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.030	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.77	T;T
Sift4G	Benign	0.79	T;T
Polyphen		0.0	.;B
Vest4		0.61
MVP		0.85
MPC		0.20
ClinPred		0.012	T
GERP RS		5.8
Varity_R		0.22
gMVP		0.44

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

Other links and lift over

dbSNP: rs139570786; hg19: chr11-64519958;