ClinVar Miner

Submissions for variant NM_006623.4(PHGDH):c.781G>A (p.Val261Met)

dbSNP: rs267606947
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000662195 SCV000784547 likely pathogenic Neu-Laxova syndrome 1 2018-03-05 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000004076 SCV000784548 likely pathogenic PHGDH deficiency 2018-03-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002298432 SCV002598845 uncertain significance not specified 2022-09-22 criteria provided, single submitter clinical testing Variant summary: PHGDH c.781G>A (p.Val261Met) results in a conservative amino acid change located in the D-isomer specific 2-hydroxyacid dehydrogenase, catalytic domain (IPR006139) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248336 control chromosomes (gnomAD). c.781G>A has been reported in the literature as a homozygous genotype in at least one individual affected with Phosphoglycerate Dehydrogenase Deficiency (e.g. Tabatabaie_2009 and Coskun_2009). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The variant effect resulted in approximately 22% of normal activity, and reduced substrate affinity (e.g. Tabatabaie_2009). One submitter has provided an assessment for this variant to ClinVar after 2014 without evidence for independent evaluation and classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae RCV000004076 SCV003504611 uncertain significance PHGDH deficiency 2021-09-17 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 261 of the PHGDH protein (p.Val261Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with phosphoglycerate dehydrogenase deficiency (PMID: 19235232). ClinVar contains an entry for this variant (Variation ID: 3872). 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"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PHGDH function (PMID: 19235232). 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.
GeneDx RCV003441702 SCV004169830 likely pathogenic not provided 2023-05-10 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect and show that this variant affects substrate binding and results in altered enzyme kinetics (Tabatabaie et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20196394, 19235232)
OMIM RCV000004076 SCV000024242 pathogenic PHGDH deficiency 2009-05-01 no assertion criteria provided literature only

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