Submissions for variant NM_006623.4(PHGDH):c.487C>T (p.Arg163Trp)

gnomAD frequency: 0.00001  dbSNP: rs772067625

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000436610	SCV000514112	uncertain significance	not provided	2016-10-21	criteria provided, single submitter	clinical testing	The R163W variant in the PHGDH gene has been reported previously in a patient with serine deficiency who was heterozygous for the R163W variant and heterozygous for another PHGDH variant (Brassier et al., 2016). The R163W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; Exome Variant Server). The R163W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on review of the data in the context of the 2015 ACMG standards and guidelines for the interpretation of sequence variants (Richards et al., 2015), we now interpret R163W as a variant of uncertain significance.
Invitae	RCV001833521	SCV003441724	uncertain significance	PHGDH deficiency	2022-07-06	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 163 of the PHGDH protein (p.Arg163Trp). This variant is present in population databases (rs772067625, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of phosphoglycerate dehydrogenase deficiency (PMID: 26610677). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 378360). 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg163 amino acid residue in PHGDH. Other variant(s) that disrupt this residue have been observed in individuals with PHGDH-related conditions (PMID: 24836451, 26610677, 30214071), which suggests that this may be a clinically significant amino acid residue. 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	RCV003338583	SCV004049071	uncertain significance	Neu-Laxova syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001833521	SCV004049072	uncertain significance	PHGDH deficiency	2023-04-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001833521	SCV002094681	uncertain significance	PHGDH deficiency	2020-01-16	no assertion criteria provided	clinical testing
OMIM	RCV001833521	SCV004811985	pathogenic	PHGDH deficiency	2024-04-08	no assertion criteria provided	literature only