rs121918193
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PM5PP2PP3_ModeratePP5_Very_Strong
The ENST00000359794.11(PFKM):c.116G>A(p.Arg39Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R39L) has been classified as Pathogenic.
Frequency
Consequence
ENST00000359794.11 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PFKM | NM_000289.6 | c.116G>A | p.Arg39Gln | missense_variant | 3/23 | ENST00000359794.11 | NP_000280.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PFKM | ENST00000359794.11 | c.116G>A | p.Arg39Gln | missense_variant | 3/23 | 1 | NM_000289.6 | ENSP00000352842 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251484Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135920
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461684Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6AN XY: 727150
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
Glycogen storage disease, type VII Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 39 of the PFKM protein (p.Arg39Gln). This variant is present in population databases (rs121918193, gnomAD 0.02%). This missense change has been observed in individual(s) with glycogen storage disease type VII (PMID: 27066546). ClinVar contains an entry for this variant (Variation ID: 2137355). 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 PFKM protein function with a positive predictive value of 80%. This variant disrupts the p.Arg39 amino acid residue in PFKM. Other variant(s) that disrupt this residue have been observed in individuals with PFKM-related conditions (PMID: 7513946, 8037209), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 09, 2023 | PP1, PP3, PP4, PM2_moderate, PM5 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at