Submissions for variant NM_005609.4(PYGM):c.660G>A (p.Gln220=)

gnomAD frequency: 0.00161  dbSNP: rs142234258

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000656957	SCV000231085	uncertain significance	not provided	2015-01-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000242887	SCV000311178	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000374157	SCV000373034	likely benign	Glycogen storage disease, type V	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV000656957	SCV000565454	uncertain significance	not provided	2023-06-02	criteria provided, single submitter	clinical testing	Alters the last nucleotide of the exon and is predicted to destroy the splice donor site but the effect on protein function is unclear; This variant is associated with the following publications: (PMID: 25914343, 25987006, 28967462, 34426522, 34906502)
Counsyl	RCV000374157	SCV000800207	uncertain significance	Glycogen storage disease, type V	2018-05-24	criteria provided, single submitter	clinical testing
Invitae	RCV000374157	SCV000831281	benign	Glycogen storage disease, type V	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656957	SCV001148316	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	PYGM: PS3:Moderate, PP3
Kids Neuroscience Centre, Sydney Children's Hospitals Network	RCV000374157	SCV001571512	likely pathogenic	Glycogen storage disease, type V		criteria provided, single submitter	clinical testing	Detected two abnormal splicing events: (1) In-frame exon 5 skipping (r.529_660del). This event removes 44 amino acids from the glycogen phosphorylase domain of PYGM (p.(Met177_Gln220del)), of which 26 residues are conserved to Caenorhabditis elegans, (2) Exon 4 and exon 5 skipping (r.425_660del). This event induces a frameshift and encodes a premature termination codon (p.(Ala142Glyfs*32)). These transcripts are predicted to be targeted by nonsense-mediated decay (NMD). Any mis-spliced PYGM transcripts that escape NMD encode PYGM protein lacking 701 amino acids from the C-terminus, including 697 residues from the glycogen phosphorylase domain.
Genome-Nilou Lab	RCV000374157	SCV001737303	uncertain significance	Glycogen storage disease, type V	2021-06-10	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000374157	SCV002059588	uncertain significance	Glycogen storage disease, type V	2018-05-14	criteria provided, single submitter	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001813765	SCV002061306	pathogenic	Tip-toe gait	2021-12-14	criteria provided, single submitter	clinical testing	The Gln220= variant in PYGM does not lead to an amino acid exchange in the protein, but according to calculations by the prediction program varSEAK it could very likely lead to the generation of a new cryptic 5' donor splice site that would change the splice mechanism in intron 5. The variant was described in combination with another PYGM variant in a case report in a patient with symptoms of McArdle disease and multiple sclerosis [Zoccolella(2015) Neurol Sci 36(9):1721-3].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000242887	SCV002511720	uncertain significance	not specified	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: Variant summary: PYGM c.660G>A (p.Gln220Gln) alters a conserved nucleotide located to the last nucleotide of exon 5, and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: four predict the variant weakens a 5' donor site. A recent publication reported experimental evidence that this variant affects mRNA splicing, demonstrating in-frame exon 5 skipping and out-of-frame exon 4-5 skipping, from whole blood derived RNA samples that were isolated from heterozygous carriers, however, the degree of mis-splicing (i.e. whether complete or partial) was not specified (Bournazos_2022). The variant allele was found at a frequency of 0.0021 in 251172 control chromosomes, predominantly within the South Asian- (frequency 0.0061), Bulgarian- (0.0049) and Southern European (0.0038) subpopulations in the gnomAD database (v2.1 exomes dataset). The observed variant frequencies in these subpopulations are above 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 might be a benign polymorphism. The variant, c.660G>A, has been reported in the literature in at least three individuals affected with Glycogen Storage Disease, Type V (McArdle disease) (Zoccolella_2015, Inal-Gultekin_2017); however, in two of these reported patients who were from the same family, two co-occurring pathogenic variants were also present (although the phase was not specified), thus potentially explaining the phenotype (Inal-Gultekin_2017). Additionally, the variant was reported in a case of Limb-girdle muscular dystrophy in the homozygous state (Barbosa-Gouveia_2022). These data do not provide clear conclusions about the variant significance. Eleven submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (n=1) / likely pathogenic (n=1), VUS (n=7), likely benign (n=1) / benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000374157	SCV004032508	likely pathogenic	Glycogen storage disease, type V	2023-02-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000374157	SCV001457728	uncertain significance	Glycogen storage disease, type V	2020-04-14	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000656957	SCV001799909	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000656957	SCV001809079	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000656957	SCV001972291	uncertain significance	not provided		no assertion criteria provided	clinical testing