Submissions for variant NM_006623.4(PHGDH):c.1394del (p.Leu465fs)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003012523	SCV003314559	pathogenic	PHGDH deficiency	2022-08-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PHGDH protein in which other variant(s) (p.Trp506*) have been determined to be pathogenic (PMID: 30348640; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with PHGDH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu465Argfs*17) in the PHGDH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 69 amino acid(s) of the PHGDH protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003012523	SCV003844371	likely pathogenic	PHGDH deficiency	2023-02-01	criteria provided, single submitter	clinical testing	Variant summary: PHGDH c.1394delT (p.Leu465ArgfsX17) results in a premature termination codon and is predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. Although the variant is not predicted to cause absence of the protein through nonsense mediated decay, the variant is predicted to disrupt the last 52 amino acids in the protein sequence. Downstream missense variants have been classified as pathogenic by our lab, suggesting that the disrupted region is important for normal protein function (e.g. c.1468G>A [p.Val490Met]). The variant was absent in 251444 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1394delT in individuals affected with Phosphoglycerate Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. 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.
Genome-Nilou Lab	RCV003340589	SCV004049132	likely pathogenic	Neu-Laxova syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003012523	SCV004049133	likely pathogenic	PHGDH deficiency	2023-04-11	criteria provided, single submitter	clinical testing