rs119103251

Positions:

• chr11-64757826-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5 PP3_Strong PP5_Very_Strong

The ENST00000164139.4(PYGM):​c.613G>A​(p.Gly205Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,614,158 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G205D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: PYGM ENST00000164139.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 7.91

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 14 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64757826-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3362481.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 11-64757826-C-T is Pathogenic according to our data. Variant chr11-64757826-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64757826-C-T is described in Lovd as [Pathogenic]. Variant chr11-64757826-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGM	NM_005609.4	c.613G>A	p.Gly205Ser	missense_variant	5/20	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.349G>A	p.Gly117Ser	missense_variant	3/18		NP_001158188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4	c.613G>A	p.Gly205Ser	missense_variant	5/20	1	NM_005609.4	ENSP00000164139	P1
PYGM	ENST00000377432.7	c.349G>A	p.Gly117Ser	missense_variant	3/18	2		ENSP00000366650

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251264 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135874

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000344 AC: 503 AN: 1461846 Hom.: 2 Cov.: 39 AF XY: 0.000362 AC XY: 263 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000410

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74462

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000247 Hom.: 0

Bravo AF: 0.000234

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type V Pathogenic:10 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 16, 2018	Across a selection of available literature, the PYGM c.613G>A (p.Gly205Ser) missense variant has been reported in at least 14 homozygotes and 20 compound heterozygotes with glycogen storage disease type V (also known as McArdle disease) (Tsujino et al. 1993; Rubio et al. 2007; Lucia et al. 2012). Control data are unavailable for the p.Gly205Ser variant, which is reported at a frequency of 0.000349 in the European American population of the Exome sequencing project. In functional studies, overexpression of GFP-Gly205Ser-PYGM resulted in significant mislocalisation and aggregation of the altered protein to the perinuclear membrane region of CHO cells (Birch et al. 2013). Based on the collective evidence, the PYGM p.Gly205Ser 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	Baylor Genetics	Mar 21, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 09, 2021	Variant summary: PYGM c.613G>A (p.Gly205Ser) 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. The variant allele was found at a frequency of 0.00012 in 251264 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PYGM causing Glycogen Storage Disease, Type V (0.00012 vs 0.0035), allowing no conclusion about variant significance. c.613G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Glycogen Storage Disease, Type V (McArdle disease), and was described as the second most common pathogenic variant in the Caucasian population (see e.g. Tsujino_1993, Martin_2001, Vieitez_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in decreased protein expression, together with an extensive aggregation of the variant protein in the perinuclear region (Birch_2012). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Feb 04, 2022	This sequence change in PYGM is predicted to replace glycine with serine at codon 205, p.(Gly205Ser). The glycine residue is highly conserved (100 vertebrates, UCSC), and is not located in an annotated functional domain. There is a small physicochemical difference between glycine and serine. The highest population minor allele frequency in gnomAD v2.1 is 0.02% (27/129,004 alleles) in the European (non-Finnish) population, which is consistent with a recessive condition. This variant is the second most common variant identified in caucasian individuals with glycogen storage disease type V. It has been detected in the homozygous and compound heterozygous states in individuals with myophosphorylase deficiency, and has been reported to segregate with disease (PMID: 8316268, 34534370). In vitro functional assays in Chinese hamster ovary cells showed misfolding and accelerated protein turnover indicating that this variant impacts protein function (PMID: 22818872). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3_Supporting, PM2_Supporting, PP1, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 18, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 205 of the PYGM protein (p.Gly205Ser). This variant is present in population databases (rs119103251, gnomAD 0.02%). This missense change has been observed in individual(s) with McArdle disease (PMID: 8316268, 17221871, 17404776, 17630210, 19251976). 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.Gly204Ser. ClinVar contains an entry for this variant (Variation ID: 2299). 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 80%. Experimental studies have shown that this missense change affects PYGM function (PMID: 22818872). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2021	Functional studies demonstrate that the G205S variant results in undetectable PYGM protein levels (Birch et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10382912, 8316268, 31980526, 30316539, 30415384, 19433441, 17915571, 22818872, 25240406, 11706962, 10382911, 7603523, 19251976) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 04, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	.;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.99
MVP		0.97
MPC		0.84
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.90
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs119103251; hg19: chr11-64525298;