ClinVar Miner

Submissions for variant NM_006623.4(PHGDH):c.1129G>A (p.Gly377Ser)

gnomAD frequency: 0.00002  dbSNP: rs267606948
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000850583 SCV000992805 pathogenic PHGDH deficiency; Neu-Laxova syndrome 1 2017-12-31 criteria provided, single submitter clinical testing
Invitae RCV000004075 SCV001584602 pathogenic PHGDH deficiency 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 377 of the PHGDH protein (p.Gly377Ser). This variant is present in population databases (rs267606948, gnomAD 0.003%). This missense change has been observed in individual(s) with phosphoglycerate dehydrogenase deficiency (PMID: 21113737, 28135894). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3871). 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) has been performed at Invitae 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: 19235232). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001659681 SCV001874192 likely pathogenic not provided 2022-10-28 criteria provided, single submitter clinical testing Published functional studies demonstrate reduced enzyme activity (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: 19235232, 28135894, 29269105, 26960553, 21113737, 31589614, 31216405, 23564319, 32594192, 27535533, 34547701)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000004075 SCV004029011 pathogenic PHGDH deficiency 2023-07-19 criteria provided, single submitter clinical testing Variant summary: PHGDH c.1129G>A (p.Gly377Ser) results in a non-conservative amino acid change located in the D-3-phosphoglycerate dehydrogenase, ASB domain (IPR045626) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251476 control chromosomes (gnomAD). c.1129G>A has been reported in the literature in individuals affected with Phosphoglycerate Dehydrogenase Deficiency (example: Tabatabaie_2009). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Tabatabaie_2009). The following publication has been ascertained in the context of this evaluation (PMID: 21113737). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab RCV003338379 SCV004049117 likely pathogenic Neu-Laxova syndrome 1 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000004075 SCV004049118 likely pathogenic PHGDH deficiency 2023-04-11 criteria provided, single submitter clinical testing
OMIM RCV000004075 SCV000024241 pathogenic PHGDH deficiency 2009-05-01 no assertion criteria provided literature only

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