rs61736659

Positions:

• chr11-64751337-G-C

Variant summary

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

The ENST00000164139.4(PYGM):​c.1957C>G​(p.Leu653Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000507 in 1,614,182 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (5 hom.)
• Consequence: PYGM ENST00000164139.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:4
• Conservation: PhyloP100: 3.48

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=0.025466383).
• BS2: High Homozygotes in GnomAdExome4 at 5 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	Protein	UniProt
PYGM	NM_005609.4	c.1957C>G	p.Leu653Val	missense_variant	16/20	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.1693C>G	p.Leu565Val	missense_variant	14/18		NP_001158188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4	c.1957C>G	p.Leu653Val	missense_variant	16/20	1	NM_005609.4	ENSP00000164139	P1
PYGM	ENST00000377432.7	c.1693C>G	p.Leu565Val	missense_variant	14/18	2		ENSP00000366650
PYGM	ENST00000462303.1	n.281C>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000923 AC: 232 AN: 251372 Hom.: 3 AF XY: 0.000846 AC XY: 115 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000493 AC: 720 AN: 1461826 Hom.: 5 Cov.: 31 AF XY: 0.000458 AC XY: 333 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0199

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000962

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.000643 AC: 98 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74504

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.0242

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00198 Hom.: 3

Bravo AF: 0.000657

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000708 AC: 86

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 14, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 16, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 11, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2021	The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25914343) -

Tip-toe gait Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

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

-

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.025	T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	2.0	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.2	N;N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.010	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.029	.;B
Vest4		0.80
MVP		0.88
MPC		0.84
ClinPred		0.085	T
GERP RS		2.0
Varity_R		0.55
gMVP		0.74

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: rs61736659; hg19: chr11-64518809;