rs398124209
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_005609.4(PYGM):āc.1466C>Gā(p.Pro489Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P489S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_005609.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PYGM | NM_005609.4 | c.1466C>G | p.Pro489Arg | missense_variant | 12/20 | ENST00000164139.4 | |
PYGM | NM_001164716.1 | c.1202C>G | p.Pro401Arg | missense_variant | 10/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PYGM | ENST00000164139.4 | c.1466C>G | p.Pro489Arg | missense_variant | 12/20 | 1 | NM_005609.4 | P1 | |
PYGM | ENST00000377432.7 | c.1202C>G | p.Pro401Arg | missense_variant | 10/18 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251488Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135920
GnomAD4 exome AF: 0.0000787 AC: 115AN: 1461796Hom.: 0 Cov.: 32 AF XY: 0.0000756 AC XY: 55AN XY: 727212
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74360
ClinVar
Submissions by phenotype
Glycogen storage disease, type V Pathogenic:5
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 07, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Dec 04, 2022 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 05, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 19, 2023 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 18, 2017 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 20, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at