chr14-50911799-C-G
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3BP4_ModerateBS1BS2
The NM_002863.5(PYGL):āc.1900G>Cā(p.Asp634His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,614,102 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002863.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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PYGL | ENST00000216392.8 | c.1900G>C | p.Asp634His | missense_variant | Exon 16 of 20 | 1 | NM_002863.5 | ENSP00000216392.7 | ||
PYGL | ENST00000532462.5 | c.1900G>C | p.Asp634His | missense_variant | Exon 16 of 20 | 1 | ENSP00000431657.1 | |||
PYGL | ENST00000544180.6 | c.1798G>C | p.Asp600His | missense_variant | Exon 15 of 19 | 2 | ENSP00000443787.1 | |||
PYGL | ENST00000532107.2 | n.73G>C | non_coding_transcript_exon_variant | Exon 1 of 4 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00425 AC: 647AN: 152204Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.00373 AC: 939AN: 251436Hom.: 2 AF XY: 0.00356 AC XY: 484AN XY: 135876
GnomAD4 exome AF: 0.00687 AC: 10040AN: 1461780Hom.: 47 Cov.: 31 AF XY: 0.00668 AC XY: 4858AN XY: 727196
GnomAD4 genome AF: 0.00425 AC: 647AN: 152322Hom.: 2 Cov.: 32 AF XY: 0.00354 AC XY: 264AN XY: 74490
ClinVar
Submissions by phenotype
Glycogen storage disease, type VI Uncertain:5Benign:1Other:2
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The variant is observed in the gnomAD v2.1.1 ( https://gnomad.broadinstitute.org ) dataset at total allele frequency of 0.380%. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.45). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PYGL-related disorder with insufficient/conflicting evidence (PMID: 31768638 / ClinVar ID: VCV000021331). A different missense change at the same codon (p.Asp634Gly) has been reported to be associated with PYGL-related disorder (PMID: 31768638). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 634 of the PYGL protein (p.Asp634His). This variant is present in population databases (rs35026927, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with glycogen storage disease and/or PYGL-related disease (PMID: 17705025). ClinVar contains an entry for this variant (Variation ID: 21331). 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 not expected to disrupt PYGL protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Variant interpreted as Uncertain significance and reported on 12-21-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
not provided Uncertain:2Benign:1
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BS1, PP3 -
PYGL: PP3, BS2 -
PYGL-related disorder Uncertain:1
The PYGL c.1900G>C variant is predicted to result in the amino acid substitution p.Asp634His. This variant has been reported in individuals with Glycogen storage disease VI (Beauchamp et al. 2007. PubMed ID: 17705025; Aeppli et al 2019. PubMed ID: 31768638). It was also reported in the heterozygous state in two individuals with possible GSD type VI, however, no second PYGL variants were observed (Ghosh et al. 2017. PubMed ID: 28468868; Degrassi et al. 2021. PubMed ID: 32505569). This variant is reported in 0.65% of alleles in individuals of European (Non-Finnish) descent including two homozygotes in gnomAD. and while this relatively high minor allele frequency argues against pathogenicity, we have observed the c.1900G>C variant in the heterozygous state in more than twenty symptomatic patients at PreventionGenetics (Internal Data). In at least ten of these patients, we found a second potential causative variant in PYGL. Family testing for several of these patients suggests that the variants followed expected Mendelian inheritance patterns for a recessive disorder. While we suspect this variant may possibly be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at