Submissions for variant NM_000277.3(PAH):c.827T>G (p.Met276Arg)

dbSNP: rs62508722

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001375900	SCV001572865	likely pathogenic	Phenylketonuria	2018-12-10	reviewed by expert panel	curation	The c.827T>G (p.Met276Arg) variant in PAH is absent from population databases and predicted damaging by in silico models. It is a novel missense change at an amino acid residue where different pathogenic missense changes have been reported (p.Met276Val is LP in ClinVar, p.Met276Lys is LP via PAH EP). It has been reported in individuals with phenylkeonuria in the literature, although a defect in the metabolism of BH4 has not been excluded as a cause for elevated phenylalanine in any of these patients (PMID: 23932990, 15300621). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM5, PP3.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375900	SCV004038387	pathogenic	Phenylketonuria	2023-08-08	criteria provided, single submitter	clinical testing	Variant summary: PAH c.827T>G (p.Met276Arg) results in a non-conservative amino acid change located in the aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251352 control chromosomes (gnomAD). c.827T>G has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (examples: Li_2018, Wang_2018, Hillert_2020 and Hyperphenylalaninemia (Shao_PAH_CCA_2021 ). These data indicate that the variant is likely to be associated with disease. Other variants affecting this codon have been classified pathogenic in ClinVar suggesting this may be a functionally important residue (CV IDs 2152159, 102855, 102856). The following publications have been ascertained in the context of this evaluation (PMID: 15300621, 26503515, 34653385, 29499199, 32668217). ClinGen PAH Variant Curation Expert Panel has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001375900	SCV004209661	likely pathogenic	Phenylketonuria	2023-06-02	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089119	SCV000119726	not provided	not provided		no assertion provided	not provided