ClinVar Miner

Submissions for variant NM_006623.4(PHGDH):c.1258G>A (p.Glu420Lys)

gnomAD frequency: 0.00019  dbSNP: rs140979375
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781718 SCV000919985 uncertain significance not specified 2023-01-05 criteria provided, single submitter clinical testing Variant summary: PHGDH c.1258G>A (p.Glu420Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 249932 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PHGDH causing Phosphoglycerate Dehydrogenase Deficiency (0.00012 vs 0.0026), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1258G>A in individuals affected with Phosphoglycerate Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Illumina Laboratory Services, Illumina RCV001097501 SCV001253788 uncertain significance PHGDH deficiency 2018-01-12 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 RCV001097501 SCV001568160 uncertain significance PHGDH deficiency 2022-07-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 420 of the PHGDH protein (p.Glu420Lys). This variant is present in population databases (rs140979375, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PHGDH-related conditions. ClinVar contains an entry for this variant (Variation ID: 633351). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Genome-Nilou Lab RCV003338789 SCV004049126 uncertain significance Neu-Laxova syndrome 1 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001097501 SCV004049127 uncertain significance PHGDH deficiency 2023-04-11 criteria provided, single submitter clinical testing

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