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

gnomAD frequency: 0.00026  dbSNP: rs587731325

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282250	SCV000698714	uncertain significance	not specified	2022-07-06	criteria provided, single submitter	clinical testing	Variant summary: PHGDH c.1471C>T (p.Arg491Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 249902 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PHGDH causing Phosphoglycerate Dehydrogenase Deficiency (0.0001 vs 0.0026), allowing no conclusion about variant significance. c.1471C>T has been reported in the literature in a compound heterozygous individual affected with Phosphoglycerate Dehydrogenase Deficiency and in an individual affected with Macular telangiectasia type 2 (Meneret_2012, Eade_2021). These data do not allow any conclusion about variant significance. Experimental evidence evaluating an impact on protein function demonstrated the variant to have 52% of relative enzyme activity compared to wild-type (Eade_2021). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811823	SCV000952110	uncertain significance	PHGDH deficiency	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 491 of the PHGDH protein (p.Arg491Trp). This variant is present in population databases (rs587731325, gnomAD 0.02%). This missense change has been observed in individual(s) with phosphoglycerate dehydrogenase deficiency (PMID: 22393170). ClinVar contains an entry for this variant (Variation ID: 496330). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PHGDH protein function. Experimental studies have shown that this missense change affects PHGDH function (PMID: 33758422). 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 Laboratory Services, Illumina	RCV000811823	SCV001253789	uncertain significance	PHGDH 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	uncertain significance	Neu-Laxova syndrome 1		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000590257	SCV001713842	uncertain significance	not provided	2019-05-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000590257	SCV001985465	likely pathogenic	not provided	2024-08-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate p.(R491W) reduces PHGDH enzyme activity (PMID: 33758422); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22393170, 26960553, 33758422, 32594192)
Ambry Genetics	RCV002532353	SCV003683471	uncertain significance	Inborn genetic diseases	2021-09-07	criteria provided, single submitter	clinical testing	(Méneret, 2012) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005019011	SCV005646928	uncertain significance	PHGDH deficiency; Neu-Laxova syndrome 1	2024-06-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000811823	SCV002094699	uncertain significance	PHGDH deficiency	2020-01-12	no assertion criteria provided	clinical testing