ClinVar Miner

Submissions for variant NM_006623.4(PHGDH):c.1468G>A (p.Val490Met)

gnomAD frequency: 0.00006  dbSNP: rs121907987
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Total submissions: 12
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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 RCV000004071 SCV000698713 pathogenic PHGDH deficiency 2017-07-23 criteria provided, single submitter clinical testing Variant summary: The PHGDH c.1468G>A (p.Val490Met) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index). This variant was found in 13/123042 control chromosomes at a frequency of 0.0001059, which does not exceed the estimated maximal expected allele frequency of a pathogenic PHGDH variant (0.0026352). The variant has been reported in the homozygous state in numerousffected individuals, and functional studies showed the variant to result in significantly reduced enzyme activity in transfected cells as well as patient fibroblasts (Klomp_2000, Pind_2002). In addition, one reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000004071 SCV000951673 pathogenic PHGDH deficiency 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 490 of the PHGDH protein (p.Val490Met). This variant is present in population databases (rs121907987, gnomAD 0.2%). This missense change has been observed in individuals with phosphoglycerate dehydrogenase deficiency (PMID: 11055895, 11751922). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3867). 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) performed at Invitae indicates that this missense variant is not expected to disrupt PHGDH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PHGDH function (PMID: 11055895, 11751922). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000004071 SCV001135397 pathogenic PHGDH deficiency 2019-05-28 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000004071 SCV001984849 pathogenic PHGDH deficiency 2020-06-05 criteria provided, single submitter clinical testing This variant has been reported in several individuals affected with phosphoglycerate dehydrogenase deficiency and was found to segregate with the disease in related individuals (PMID: 11055895, 11751922). Functional studies have shown that this change disrupts PHGDH enzymatic activity in vitro (PMID: 11055895, 11751922). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.00014 (40/281324) and thus is presumed to be rare. In silico analyses are suggestive of deleterious effect of the c.1468G>A (p.Val490Met) variant on protein function. Based on the available evidence, the c.1468G>A (p.Val490Met) variant is classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002251869 SCV002523267 likely pathogenic See cases 2019-10-02 criteria provided, single submitter clinical testing ACMG classification criteria: PS3, PS4, PP1, PP3
Fulgent Genetics, Fulgent Genetics RCV002482824 SCV002790572 pathogenic PHGDH deficiency; Neu-Laxova syndrome 1 2022-03-19 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003338378 SCV004049138 likely pathogenic Neu-Laxova syndrome 1 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000004071 SCV004049139 likely pathogenic PHGDH deficiency 2023-04-11 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV003338378 SCV005329503 pathogenic Neu-Laxova syndrome 1 2023-05-20 criteria provided, single submitter clinical testing The observed missense variant c.1468G>A(p.Val490Met) in PHGDH gene has been reported previously in homozygous state in multiple indidviduals with 3-phosphoglycerate dehydrogenase (PHGDH) deficiency (Klomp LW, et al., 2000, Pind S, et al., 2002). Experimental studies show that the variant results in significantly reduced enzyme activity in transfected cells as well as patient fibroblasts (Klomp LW, et al., 2000, Pind S, et al., 2002). The c.1468G>A variant has 0.01% allele frequency in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid Valine at position 490 is changed to a Methionine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen, SIFT and Mutation Taster) predict no damaging effect on protein structure and function for this variant. The amino acid change p.Val490Met in PHGDH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed.
OMIM RCV000004071 SCV000024237 pathogenic PHGDH deficiency 2000-12-01 no assertion criteria provided literature only
Natera, Inc. RCV000004071 SCV001461724 pathogenic PHGDH deficiency 2020-09-16 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004757095 SCV005349403 pathogenic PHGDH-related disorder 2024-08-19 no assertion criteria provided clinical testing The PHGDH c.1468G>A variant is predicted to result in the amino acid substitution p.Val490Met. This variant has been reported in individuals with autosomal recessive 3-phosphoglycerate dehydrogenase deficiency (Klomp et al. 2000. PubMed ID: 11055895; Ni et al. 2019. PubMed ID: 31903955; Lindstrand et al. 2022. PubMed ID: 36066546). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.

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