ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs398124209
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Total submissions: 8
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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 2024-09-20 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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: 19472443, 21658951, 25914343, 34534370)
Labcorp Genetics (formerly Invitae), Labcorp RCV001047041 SCV001210973 pathogenic Glycogen storage disease, type V 2024-06-20 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.
Fulgent Genetics, Fulgent Genetics RCV001047041 SCV005684133 likely pathogenic Glycogen storage disease, type V 2024-04-06 criteria provided, single submitter clinical testing
Natera, Inc. RCV001047041 SCV001461280 likely pathogenic Glycogen storage disease, type V 2020-09-16 no assertion criteria provided clinical testing

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