Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
RCV000402510 | SCV000397100 | uncertain significance | Glycogen storage disease IXb | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
Invitae | RCV000402510 | SCV003519740 | uncertain significance | Glycogen storage disease IXb | 2022-04-23 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1089 of the PHKB protein (p.Pro1089Arg). This variant is present in population databases (rs763764574, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of glycogen storage disease (PMID: 30919572). ClinVar contains an entry for this variant (Variation ID: 319366). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003488536 | SCV004241992 | uncertain significance | not specified | 2023-12-08 | criteria provided, single submitter | clinical testing | Variant summary: PHKB c.3266C>G (p.Pro1089Arg) results in a non-conservative amino acid change located in the C-terminal domain (IPR045583) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-05 in 1607020 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in PHKB causing Glycogen Phosphorylase Kinase Deficiency (0.0011), allowing no conclusion about variant significance. c.3266C>G has been reported in the literature in a homozygous individual affected with symptoms of Glycogen Phosphorylase Kinase Deficiency (Al-Dewik_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30919572). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |