Submissions for variant NM_002591.4(PCK1):c.925G>A (p.Gly309Arg)

gnomAD frequency: 0.00105  dbSNP: rs201186470

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000509043	SCV000434502	uncertain significance	Phosphoenolpyruvate carboxykinase deficiency, cytosolic	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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000509043	SCV001149868	pathogenic	Phosphoenolpyruvate carboxykinase deficiency, cytosolic	2019-09-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861168	SCV002224297	uncertain significance	not provided	2022-02-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 309 of the PCK1 protein (p.Gly309Arg). This variant is present in population databases (rs201186470, gnomAD 1.2%). This missense change has been observed in individual(s) with cytosolic phosphoenolpyruvate carboxykinase deficiency (PMID: 28216384, 33445193). ClinVar contains an entry for this variant (Variation ID: 338886). 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. Experimental studies have shown that this missense change affects PCK1 function (PMID: 28216384). 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.
Mendelics	RCV000509043	SCV002517861	pathogenic	Phosphoenolpyruvate carboxykinase deficiency, cytosolic	2022-05-04	criteria provided, single submitter	clinical testing
Department of Human Genetics, University Hospital Bern, Inselspital	RCV000509043	SCV005619945	pathogenic	Phosphoenolpyruvate carboxykinase deficiency, cytosolic	2024-11-29	criteria provided, single submitter	clinical testing	This variant is present population databases at a frequency of 0.06% (gnomAD v4.1) has been described as disease-causing in several affected homozygous or compound heterozygous individuals with phosphoenolpyruvate carboxykinase deficiency (e.g. Vieira et al. 2017, PMID: 28216384; Becker et al. 2021, PMID: 33445193). Functional studies have shown that this missense change affects PCK1 function (Vieira et al. 2017, PMID: 28216384). In addition, In silico prediction (REVEL) predicts a deleterious effect for this variant.
OMIM	RCV000509043	SCV000606824	pathogenic	Phosphoenolpyruvate carboxykinase deficiency, cytosolic	2023-04-12	no assertion criteria provided	literature only