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

gnomAD frequency: 0.00006  dbSNP: rs121907987

Total submissions: 12

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.