ClinVar Miner

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

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Total submissions: 4
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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

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