Submissions for variant NM_005609.4(PYGM):c.1466C>G (p.Pro489Arg)

gnomAD frequency: 0.00004  dbSNP: rs398124209

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081305	SCV000225627	pathogenic	not provided	2013-09-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000081305	SCV000576835	likely pathogenic	not provided	2017-04-18	criteria provided, single submitter	clinical testing	The P489R variant has been reported previously in patients with McArdle disease (Duno et al. 2009; Miteff et al. 2011). The P489R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P489R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret P489R as likely pathogenic.
Invitae	RCV001047041	SCV001210973	pathogenic	Glycogen storage disease, type V	2023-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 489 of the PYGM protein (p.Pro489Arg). This variant is present in population databases (rs398124209, gnomAD 0.002%). This missense change has been observed in individual(s) with McArdle disease (PMID: 19472443, 21658951). It has also been observed to segregate with disease in related individuals. This variant is also known as Pro488Arg. ClinVar contains an entry for this variant (Variation ID: 95291). 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 95%. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001047041	SCV003810387	pathogenic	Glycogen storage disease, type V	2024-01-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001047041	SCV004207209	likely pathogenic	Glycogen storage disease, type V	2023-12-19	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV001047041	SCV004812400	pathogenic	Glycogen storage disease, type V	2022-12-04	criteria provided, single submitter	clinical testing	This sequence change in PYGM is predicted to replace proline with arginine at codon 489, p.(Pro489Arg). The proline residue is highly conserved (100 vertebrates, UCSC), and is not located in an annotated domain. There is a large physicochemical difference between proline and arginine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.002% (3/129,186 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant has been detected compound heterozygous with a second pathogenic variant in multiple individuals with a clinical diagnosis of glycogen storage disease type V (PMID: 19472443, 34534370). 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, PM2_Supporting, PP3.
Natera, Inc.	RCV001047041	SCV001461280	likely pathogenic	Glycogen storage disease, type V	2020-09-16	no assertion criteria provided	clinical testing