Submissions for variant NM_000277.3(PAH):c.466G>C (p.Ala156Pro)

dbSNP: rs199475686

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV003479002	SCV004222622	pathogenic	Phenylketonuria	2023-12-30	reviewed by expert panel	curation	The c.466G>C (p.Ala156Pro) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 26322415). This variant is absent in population databases. This variant was detected in trans with multiple pathogenic variants: p.H220P (PMID 26322415); c.611A>G (aka EX6-96A>G, PMID: 26600521); p.V5Sfs*33, p.R158W, p.R241C (2 patients), p.R261Q, p.R400T, p.T418P (PMID: 30050108). Functional studies show the PAH A156P mutant produces reduced protein (8.7% of wild type), with a residual enzyme activity of 10.4% (PMID 24327145). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2_supporting, PP4_Moderate, PS3_supporting.
Mayo Clinic Laboratories, Mayo Clinic	RCV000088936	SCV005414120	pathogenic	not provided	2024-06-20	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PM3_very_strong, PS3_supporting
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV003479002	SCV005416849	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PM2_Supporting+PS3_Supporting+PM3_VeryStrong+PP4
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088936	SCV000119536	not provided	not provided		no assertion provided	not provided