rs116987552

Positions:

• chr11-64759751-G-A
• chr11-64759751-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_005609.4(PYGM):​c.148C>T​(p.Arg50Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,614,240 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (10 hom.)
• Consequence: PYGM NM_005609.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:33 O:1
• Conservation: PhyloP100: 2.56

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-64759751-G-A is Pathogenic according to our data. Variant chr11-64759751-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64759751-G-A is described in Lovd as [Pathogenic]. Variant chr11-64759751-G-A is described in Lovd as [Pathogenic]. Variant chr11-64759751-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGM	NM_005609.4	c.148C>T	p.Arg50Ter	stop_gained	1/20	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.148C>T	p.Arg50Ter	stop_gained	1/18		NP_001158188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4	c.148C>T	p.Arg50Ter	stop_gained	1/20	1	NM_005609.4	ENSP00000164139	P1
PYGM	ENST00000377432.7	c.148C>T	p.Arg50Ter	stop_gained	1/18	2		ENSP00000366650

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152240 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00145 AC: 365 AN: 251452 Hom.: 0 AF XY: 0.00145 AC XY: 197 AN XY: 135906

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00295 AC: 4312 AN: 1461882 Hom.: 10 Cov.: 31 AF XY: 0.00279 AC XY: 2030 AN XY: 727240

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000580

Gnomad4 NFE exome AF: 0.00366

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152358 Hom.: 2 Cov.: 33 AF XY: 0.00166 AC XY: 124 AN XY: 74500

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00312

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00221 Hom.: 0

Bravo AF: 0.00189

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00137 AC: 166

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:33 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type V Pathogenic:19 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jan 12, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 27, 2018	The p.Arg50X variant in PYGM is a known pathogenic variant that has been report ed in at least 50 homozygotes and 29 compound heterozygous with glycogen storage disease type V (GSDV), also known as McArdle disease, and segregated with disea se in 5 affected siblings from 4 families (Tsujino 1993, Gurgel-Giannetti 2013, deLuna 2014, and Hongrel 2015). Mouse models demonstrate that this variant cause s glycogen storage disease type V (Nogales-Gadea 2012 and Brull 2015). It has al so been reported in ClinVar (Variation ID 2298) by multiple laboratories as path ogenic and has been identified in 0.20% (318/126684) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be co nsistent with a recessive carrier frequency. In summary, this variant meets crit eria to be classified as pathogenic for autosomal recessive GSDV based upon case observations, segregation studies, and animal models. ACMG/AMP Criteria applied : PVS1, PM3_Very Strong, PS3, PP1_Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 06, 2021	The PYGM c.148C>T variant is classified as Pathogenic (PVS1, PS3, PS4, PM3) The PYGM c.148C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 50 (PVS1). The variant has been reported in probands with a clinical presentation of OMIM:232600 ( Reported multiple times in OMIM:608455 ) (PS4). Well-established functional studies show a deleterious effect of this variant ( Nogales-Gadea (2012) PubMed: 22730558 Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease ) (PS3). This variant has been detected in trans with a pathogenic variant for this recessive condition (PM3). Identified in another case as compound het with a second pathogenic variant in PYGM (c.613G>A;p.Gly205Ser). This variant was shown to be maternally inherited and the c.613G>A variant is paternally inherited in that case. The variant has been reported in dbSNP (rs116987552) and in the HGMD database: CM930629. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 2298). -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 22, 2023	Variant summary: PYGM c.148C>T (p.Arg50X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.0015 in 251452 control chromosomes in gnomAD. This frequency is not significantly higher than estimated for a pathogenic variant in PYGM causing Glycogen Storage Disease Type V, also known as McArdle disease, (0.0015 vs 0.0035), allowing no conclusion about variant significance. c.148C>T has been reported in the literature in individuals affected with Glycogen Storage Disease Type V (example: Cerino_2022). These data indicate that the variant is very likely associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 35741838). Twenty submitters have cited clinical-significance assessments (all pathogenic) for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 22, 2022	This sequence change creates a premature termination codon at position 50 in exon 1 (of 20) of PYGM, p.(Arg50*). This alteration is expected to result in nonsense-mediated decay in a gene where loss of function is a known mechanism of disease. The variant is present in a large population cohort at a frequency of 0.15% (rs116987552, 424/282,854 alleles, 0 homozygotes in gnomAD v2.1), and is the most common pathogenic variant associated with glycogen storage disease type V (also known as McArdle disease) in the European population. The variant has been identified as homozygous and compound heterozygous with a second pathogenic allele in many cases with a clinical diagnosis of McArdle disease (PMID: 8316268). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Jul 19, 2023	ACMG Criteria: PVS1, PS3, PS4, PM3, PP1, PP5; Variant was found in compound heterozygous state with NM_005609.4:c.1477del. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Feb 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The PYGM c.148C>T (p.Arg50Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg50Ter variant is the most commonly identified variant in patients with glycogen storage disease type V, also known as McArdle disease, in the majority of populations studied (Martin et al. 2006; Nogales-Gadea et al. 2015). Across a selection of the available literature, the p.Arg50Ter variant is detected with an allele frequency ranging from 43%-78% in the respective patient cohorts (Tsujino et al. 1993; Bruno et al. 2006; Aquaron et al. 2007; Deschauer et al. 2007; Vieitez et al. 2011; Gurgel-Giannetti et al. 2013). The variant was absent from 96 healthy individuals but is reported at a frequency of 0.00314 in the European American population of the Exome Sequencing Project. A knock-in mouse model homozygous for the p.Arg50Ter variant displays a McArdle disease-like phenotype (Nogales-Gadea et al. 2012). Based on the collective evidence, the p.Arg50Ter variant is classified as pathogenic for glycogen storage disease type V. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	The c.148C>T;p.(Arg50*) variant creates a premature translational stop signal in the PYGM gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 2298; PMID: 20301518; PMID: 23653251; PMID: 17324573; PMID: 12929201; PMID:20301518) - PS4. The variant is present at low allele frequencies population databases (rs116987552 – gnomAD 0.01499%; ABraOM 0.001708 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg50*) was detected in trans with a pathogenic variant (PMID: 23653251; PMID: 17324573) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 05, 2024	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with McArdle disease (MIM#232600). (I) 0106 - This gene is associated with autosomal recessive disease. However, a single family has been reported for an autosomal dominant glycogen storage disorder (PMID: 32386344). (I) 0115 - Variants in this gene are known to have variable expressivity. Some affected individuals have minimal symptoms with essentially no limitations in activities of daily living. This may be attributed to variable physical activity habits (Gene Reviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 253 heterozygotes, 1 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Several NMD-predicted variants have been reported in patients with McArdle disease (MIM#232600) (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in several McArdle disease (MIM#232600) patients in both homozygous and compound heterozygous states (ClinVar; PMID: 29143597). (SP) 1205 - This variant has been shown to be maternally inherited (VCGS #20G001969). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Arg50*) in the PYGM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PYGM are known to be pathogenic (PMID: 8316268, 16786513). This variant is present in population databases (rs116987552, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with McArdle disease (PMID: 8316268, 16786513, 21802952, 22250184, 23653251). ClinVar contains an entry for this variant (Variation ID: 2298). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PYGM function (PMID: 22730558). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	PYGM: PM3:Very Strong, PVS1, PM2, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2019	Mouse model, homozygous for R50X, found to have undetectable myophosphorylase protein and enzyme activity in skeletal muscle as well as massive muscle glycogen accumulation (Brull et al., 2015); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25873271, 31980526, 32124677, 31517061, 29961518, 30609409, 30316539, 30415384, 29382405, 22995991, 22344438, 20981092, 18667317, 10918252, 9120482, 27899787, 27300253, 26670295, 27031745, 22730558, 27030740, 22818872, 8316268, 17404776, 25741863, 26240973, 25240406, 25914343, 23653251) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Oct 29, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PYGM p.R50* variant is a well-known pathogenic variant known to cause McArdle disease and is the most common pathogenic variant in individuals of European and US descent (Martin_2019_PMID:20301518). The variant was identified in dbSNP (ID: rs116987552), ClinVar (classified as pathogenic by Counsyl, Ambry Genetics, GeneDx, EGL Genetic Diagnostics, Invitae, Laboratory for Molecular Medicine, Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Fulgent Genetics, Illumina and Molecular Diagnostics Lab, Nemours Alfred I. duPont Hospital for Children) and LOVD 3.0 (classified as pathogenic). The variant was identified in control databases in 424 of 282854 chromosomes at a frequency of 0.001499 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 325 of 129154 chromosomes (freq: 0.002516), Other in 18 of 7226 chromosomes (freq: 0.002491), Latino in 48 of 35440 chromosomes (freq: 0.001354), African in 18 of 24972 chromosomes (freq: 0.000721), European (Finnish) in 12 of 25122 chromosomes (freq: 0.000478), Ashkenazi Jewish in 1 of 10370 chromosomes (freq: 0.000096), East Asian in 1 of 19954 chromosomes (freq: 0.00005), and South Asian in 1 of 30616 chromosomes (freq: 0.000033). The c.148C>T variant leads to a premature stop codon at position 50 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PYGM gene are an established mechanism of disease in McArdle disease and is the type of variant known to cause the disorder in the homozygous or compound heterozygous state. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Mouse models with the p.R50* variant display a McArdle disease phenotype (Nogales-Gadea_2012_PMID:22730558; Brull_2015_PMID: 25873271). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 22, 2021	PM2, PVS1 -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Dec 13, 2023	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2014

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jun 24, 2020

ACMG classification criteria: PVS1, PS3, PS4, PM3, PP1 -

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

Dec 19, 2022

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. -

Muscular atrophy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Columbia University Laboratory of Personalized Genomic Medicine, Columbia University Medical Center

Oct 18, 2021

The c.148C>T (p.Arg50Ter) variant in PYGM identified in this individual is one of the most common, well established, pathogenic variants described in PYGM (Nogales-Gadea et al., 2015). To date, this variant has eleven independent pathogenic curations in ClinVar (VarID:2298). Sequencing and RT-PCR studies have suggested that the c.148C>T variant is subject to nonsense mediated decay as mature cDNA transcript were not detected from this allele in individuals harboring these variant (Nogales-Gadea et al., 2008). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.0019
FATHMM_MKL	Uncertain	0.76	D
MutationTaster	Benign	1.0	A;A
Vest4		0.64
GERP RS		2.4

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: rs116987552; hg19: chr11-64527223;