NM_005609.4:c.1094C>T

Variant names:

• chr11-64754024-G-A
• rs116135678
• NM_005609.4:c.1094C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_005609.4(PYGM):​c.1094C>T​(p.Ala365Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000875 in 1,601,044 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00089 (1 hom.)
• Consequence: PYGM NM_005609.4 missense, splice_region
• Scores: Splicing: ADA: 0.9843
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:8
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 11-64754024-G-A is Pathogenic according to our data. Variant chr11-64754024-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203394.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=5, Pathogenic=3}. Variant chr11-64754024-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGM	NM_005609.4	c.1094C>T	p.Ala365Val	missense_variant, splice_region_variant	Exon 10 of 20	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.830C>T	p.Ala277Val	missense_variant, splice_region_variant	Exon 8 of 18		NP_001158188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4	c.1094C>T	p.Ala365Val	missense_variant, splice_region_variant	Exon 10 of 20	1	NM_005609.4	ENSP00000164139.3
PYGM	ENST00000377432.7	c.830C>T	p.Ala277Val	missense_variant, splice_region_variant	Exon 8 of 18	2		ENSP00000366650.3
PYGM	ENST00000460413.1	n.171C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152184 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000711 AC: 160 AN: 224920 Hom.: 0 AF XY: 0.000797 AC XY: 97 AN XY: 121746

Gnomad AFR exome AF: 0.000218

Gnomad AMR exome AF: 0.000908

Gnomad ASJ exome AF: 0.00105

Gnomad EAS exome AF: 0.0000594

Gnomad SAS exome AF: 0.000142

Gnomad FIN exome AF: 0.0000525

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.000890 AC: 1290 AN: 1448742 Hom.: 1 Cov.: 37 AF XY: 0.000872 AC XY: 627 AN XY: 719410

Gnomad4 AFR exome AF: 0.000271

Gnomad4 AMR exome AF: 0.00129

Gnomad4 ASJ exome AF: 0.000811

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000142

Gnomad4 FIN exome AF: 0.0000963

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.000951

GnomAD4 genome AF: 0.000729 AC: 111 AN: 152302 Hom.: 0 Cov.: 31 AF XY: 0.000591 AC XY: 44 AN XY: 74482

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00104 Hom.: 1

Bravo AF: 0.000718

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000669 AC: 81

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease, type V Pathogenic:6 Uncertain:4

Jun 30, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala365Val variant in PYGM has been reported, in the compound heterozygous state, in over 5 individuals with Glycogen Storage Disease, Type V (McArdle disease ) (Vieitez 2011 PMID: 21802952, Rubio 2007 PMID: 17630210, Bruno 2006 PMID: 16786513, Lucia 2012 PMID: 22250184, Inal-Gultekin 2017 PMID: 28967462, Santalla 2017 PMID: 29143597). This variant has been reported in ClinVar (Variation ID 203394) and it has been identified in 71/68026 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Glycogen Storage Disease, Type V. ACMG/AMP Criteria applied: PM3_Very Strong, PP3. -

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 365 of the PYGM protein (p.Ala365Val). This variant is present in population databases (rs116135678, gnomAD 0.1%), 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: 17221871, 29143597; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203394). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). 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. -

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 27, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The variant (c.1094C>T; p.A365V) is considered to be likely pathogenic because it has been reported in several patients with biochemically proven McArdle disease across multiple cohorts and has been modeled to occur in a very densely packed and critical region of the gene for glycogen binding (PMID: 21802952; 17630210; 17221871). It occurs at low frequencies in ExAC (allele frequency of 65 out of 62854 alleles, 0.1%). The variant occurs in highly conserved amino acid and nucleotide positions but not in a functional domain. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PYGM c.1094C>T (p.Arg365Val) missense variant has been reported in four studies in which it is found in a compound heterozygous state in five patients with glycogen storage disease type V, and in two additional patient alleles of unknown zygosity (Bruno et al. 2006; Rubio et al. 2007; Rubio et al. 2007; Lucia et al. 2012). The p.Arg365Val variant was absent from 246 controls but is reported at a frequency of 0.00851 in the other population of the Exome Aggregation Consortium. The Arg365 variant is located in a highly conserved region of the protein (Rubio et al. 2007). Based on the evidence the p.Arg365Val variant is classified as likely pathogenic for glycogen storage disease type V. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Nov 08, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 27, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PYGM c.1094C>T (p.Ala365Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 5 donor site. One predict the variant strengthens a 5 donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00071 in 224920 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PYGM causing Glycogen Storage Disease, Type V (0.00071 vs 0.0035), allowing no conclusion about variant significance. c.1094C>T has been reported in the literature in multiple compound heterozygous individuals affected with Glycogen Storage Disease, Type V (Vieitez_2011, Rubio_2007, Bruno_2006, Lucia_2012, Inal-Gultekin_2017, Santalla_2017, Lkken_2023). These data indicate that the variant is very likely to be associated with disease. 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: 25741863, 16786513, 28967462, 37769369, 22250184, 17221871, 29143597, 21802952). ClinVar contains an entry for this variant (Variation ID: 203394). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 10, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Uncertain:4

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PYGM: PM2, PM3 -

Feb 10, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4_moderate, PM2, PP3, PP4 -

Oct 26, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed multiple times with a pathogenic variant in unrelated patients with McArdle disease in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosome (PMID: 17630210, 29143597); 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: 21802952, 20981092, 16786513, 22250184, 34426522, 25741863, 29907799, 28967462, 30011114, 29143597, 38516404, 37769369, Passetti2024[Preprint], 17221871, 17630210) -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PYGM p.Ala277Val variant was identified in 5 of 666 proband chromosomes (frequency: 0.0075) from individuals with McArdle disease (Santalla_2017_PMID:29143597). The variant was identified in dbSNP (ID: rs116135678) and ClinVar (classified as uncertain significance by Invitae and EGL Genetics and as likely pathogenic by Illumina and Division of Human Genetics, Children's Hospital of Philadelphia). The variant was also identified in control databases in 172 of 256272 chromosomes at a frequency of 0.0006712 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 10 of 9824 chromosomes (freq: 0.001018), European (non-Finnish) in 115 of 115330 chromosomes (freq: 0.000997), Latino in 30 of 32778 chromosomes (freq: 0.000915), Other in 6 of 6708 chromosomes (freq: 0.000895), African in 5 of 22454 chromosomes (freq: 0.000223), South Asian in 4 of 28262 chromosomes (freq: 0.000142), East Asian in 1 of 18386 chromosomes (freq: 0.000054), and European (Finnish) in 1 of 22530 chromosomes (freq: 0.000044). The p.Ala277 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence however three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Tip-toe gait Pathogenic:1

Jan 11, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	.;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	.;H
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.86
MVP		0.98
MPC		0.66
ClinPred		0.26	T
GERP RS		4.8
Varity_R		0.91
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.84
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: rs116135678; hg19: chr11-64521496; COSMIC: COSV99377397; COSMIC: COSV99377397;