rs776680924
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_005609.4(PYGM):c.347T>C(p.Leu116Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L116V) has been classified as Uncertain significance.
Frequency
Consequence
NM_005609.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PYGM | ENST00000164139.4 | c.347T>C | p.Leu116Pro | missense_variant, splice_region_variant | Exon 3 of 20 | 1 | NM_005609.4 | ENSP00000164139.3 | ||
PYGM | ENST00000377432.7 | c.244-248T>C | intron_variant | Intron 1 of 17 | 2 | ENSP00000366650.3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152106Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000478 AC: 12AN: 251268 AF XY: 0.0000368 show subpopulations
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461832Hom.: 0 Cov.: 34 AF XY: 0.0000179 AC XY: 13AN XY: 727200 show subpopulations
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74292 show subpopulations
ClinVar
Submissions by phenotype
Glycogen storage disease, type V Pathogenic:3Uncertain:2
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This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 116 of the PYGM protein (p.Leu116Pro). This variant is present in population databases (rs776680924, gnomAD 0.1%). This missense change has been observed in individual(s) with glycogen storage disease and/or McArdle disease (PMID: 10417800, 29143597, 30011114, 34215481; internal data). This variant is also known as L115P. ClinVar contains an entry for this variant (Variation ID: 551567). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at