Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000823090 | SCV000963933 | likely pathogenic | Glycogen storage disease IXa1 | 2022-11-08 | 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.Gly1210 amino acid residue in PHKA2. Other variant(s) that disrupt this residue have been observed in individuals with PHKA2-related conditions (PMID: 32244026), which suggests that this may be a clinically significant amino acid residue. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PHKA2 protein function. ClinVar contains an entry for this variant (Variation ID: 664908). This missense change has been observed in individuals with glycogen storage disease type IXa (PMID: 11286390, 31508908; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1210 of the PHKA2 protein (p.Gly1210Glu). |
| Victorian Clinical Genetics Services, |
RCV000823090 | SCV002767399 | likely pathogenic | Glycogen storage disease IXa1 | 2021-05-06 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely pathogenic. 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Glycogen storage disease, type IXa1 and type IXa2. (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Gly1210Arg) variant has been reported as a VUS in a one-year-old patient with GSD type IXa1 (PMID: 32244026). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has previously been reported in two GSD type IXa1 patients but has also been classified as a VUS (PMID: 11286390, PMID: 31508908, ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |