Submissions for variant NM_006623.4(PHGDH):c.2T>C (p.Met1Thr)

dbSNP: rs951372478

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001806759	SCV002051138	likely pathogenic	PHGDH deficiency	2021-12-15	criteria provided, single submitter	clinical testing	Variant summary: PHGDH c.2T>C (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next alternative downstream in-frame start codon (Met 96) is located at the end of exon 2. Therefore, a severe outcome is predicted. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251114 control chromosomes. To our knowledge, no occurrence of c.2T>C in individuals affected with Phosphoglycerate Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. However, the HGMD database lists at-least one other variant resulting in the same translational impact, namely c.1A>C (p.M1?) that has been associated with a phenotype of Neu-Laxova syndrome, an allelic autosomal recessive disorder with a more severe phenotype that usually results in neonatal death. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001806759	SCV002152516	pathogenic	PHGDH deficiency	2022-02-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1331415). Disruption of the initiator codon has been observed in individual(s) with Neu-Laxova syndrome (PMID: 30838783). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the PHGDH mRNA. The next in-frame methionine is located at codon 96.
Genome-Nilou Lab	RCV003339747	SCV004049029	likely pathogenic	Neu-Laxova syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001806759	SCV004049030	likely pathogenic	PHGDH deficiency	2023-04-11	criteria provided, single submitter	clinical testing