Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins Ntd Llc |
RCV000592955 | SCV000704470 | uncertain significance | not provided | 2016-12-28 | criteria provided, single submitter | clinical testing | |
Mendelics | RCV000989223 | SCV001139456 | pathogenic | Glycogen storage disease, type VI | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000989223 | SCV001534458 | likely pathogenic | Glycogen storage disease, type VI | 2021-09-18 | criteria provided, single submitter | clinical testing | 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. This variant disrupts the p.Gly233 amino acid residue in PYGL. Other variant(s) that disrupt this residue have been observed in individuals with PYGL-related conditions (PMID: 12809646; Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 499130). This missense change has been observed in individual(s) with glycogen storage disease (PMID: 31508908; Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs749922511, ExAC 0.01%). This sequence change replaces glycine with serine at codon 233 of the PYGL protein (p.Gly233Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000989223 | SCV004038082 | pathogenic | Glycogen storage disease, type VI | 2023-08-02 | criteria provided, single submitter | clinical testing | Variant summary: PYGL c.697G>A (p.Gly233Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251430 control chromosomes (gnomAD). c.697G>A has been reported in the literature in individuals affected with Glycogen storage disease, type VI (examples: Sperb-Ludwig_2019, Lu_2020, and Grunert_2021). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same residue (p.Gly233Asp) has been classified as pathogenic in ClinVar suggesting this residue may be functionally important (CV ID 21339). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=2) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. |