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

gnomAD frequency: 0.00002  dbSNP: rs267606948

Total submissions: 7

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