ClinVar Miner

Submissions for variant NM_006623.4(PHGDH):c.1471C>T (p.Arg491Trp) (rs587731325)

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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 RCV000590257 SCV000698714 uncertain significance not provided 2016-10-24 criteria provided, single submitter clinical testing Variant summary: The c.1471C>T (p.Arg491Thr) in PHGDH gene is a missense change that involves a mildly conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant of interest is located outside of any known functional domain, although the functional impact of this missense change is yet to be studied. The variant is present in the large control population dataset of ExAC at a low frequency 0.000107 (13/121180 chrs tested), which does not exceed the maximal expected frequency of a pathogenic allele (0.0026) in this gene. The variant has been reported as a mild mutation in compound heterozygosity with a likely pathogenic variant in an affected individual presented with 3-PGDH deficiency (Meneret, 2012), but was not cited by any reputable database/clinical laboratory as causative. At this time there is not sufficient undeniable evidence to classify this variant with confidence. Taken together, the variant was classified as VUS until more data becomes available
Invitae RCV000811823 SCV000952110 uncertain significance Phosphoglycerate dehydrogenase deficiency 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 491 of the PHGDH protein (p.Arg491Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs587731325, ExAC 0.02%). This variant has been observed in an individual affected with phosphoglycerate dehydrogenase deficiency (PMID: 22393170). ClinVar contains an entry for this variant (Variation ID: 496330). 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: "Deleterious"; PolyPhen-2: "Benign"; 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.
Illumina Clinical Services Laboratory,Illumina RCV000811823 SCV001253789 uncertain significance Phosphoglycerate dehydrogenase deficiency 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.
Baylor Genetics RCV001334580 SCV001527461 likely pathogenic Neu-Laxova syndrome 1 2018-01-29 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic RCV000590257 SCV001713842 uncertain significance not provided 2019-05-20 criteria provided, single submitter clinical testing

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