11-64753925-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_005609.4(PYGM):c.1193C>T(p.Pro398Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000815 in 1,594,662 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P398P) has been classified as Likely benign.
Frequency
Consequence
NM_005609.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PYGM | NM_005609.4 | c.1193C>T | p.Pro398Leu | missense_variant | 10/20 | ENST00000164139.4 | |
PYGM | NM_001164716.1 | c.929C>T | p.Pro310Leu | missense_variant | 8/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PYGM | ENST00000164139.4 | c.1193C>T | p.Pro398Leu | missense_variant | 10/20 | 1 | NM_005609.4 | P1 | |
PYGM | ENST00000377432.7 | c.929C>T | p.Pro310Leu | missense_variant | 8/18 | 2 | |||
PYGM | ENST00000460413.1 | n.270C>T | non_coding_transcript_exon_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152170Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000919 AC: 2AN: 217694Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 117590
GnomAD4 exome AF: 0.00000832 AC: 12AN: 1442492Hom.: 0 Cov.: 37 AF XY: 0.00000838 AC XY: 6AN XY: 715724
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152170Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Glycogen storage disease, type V Pathogenic:2Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 22, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 05, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 398 of the PYGM protein (p.Pro398Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with glycogen storage disease (PMID: 21880526; Invitae). ClinVar contains an entry for this variant (Variation ID: 552430). 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%. 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 17, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 09, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at