Submissions for variant NM_000277.3(PAH):c.971T>A (p.Ile324Asn)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV003479543	SCV004222643	pathogenic	Phenylketonuria	2023-12-30	reviewed by expert panel	curation	The NM_000277.3:c.971T>A (p.Ile324Asn) variant is a missense variant in exon 10 of 13 of PAH. It has been previously reported in at least 12 patients with PKU and BH4 deficiency formally excluded, including in confirmed trans with Pathogenic or Likely Pathogenic variants (PM3_VeryStrong (7.5 points total); PP4_Moderate). It was reported in presumed trans with p.R241C (Pathogenic per ClinGen PAH VCEP) in a Chinese proband with mild PKU (plasma Phe 760 μmol/L) and BH4 deficiency was said to be excluded (PMID: 28982351); in presumed trans with p.R111* (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU and in presumed trans with c.509+1G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU (plasma Phe levels not specified; BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes). It has also been reported in confirmed trans with c.1066-11G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with PKU and BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 24705691); in a Chinese proband with PKU in confirmed trans with the c.442–1G>A variant (Pathogenic by ClinGen PAH VCEP) and in another Chinese proband with PKU in confirmed trans with the p.G247R variant (Likely Pathogenic by ClinGen PAH VCEP) (PMID: 29353259). It has been noted in a patient with PKU in presumed trans with p.T418P variant (Pathogenic by ClinGen PAH VCEP) (plasma Phe levels not noted; BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 29731766); in a Chinese patient with mild PKU (plasma Phe 780 umol/L) in presumed trans with the p.R243Q variant (Pathogenic by ClinGen PAH VCEP) and BH4 deficiency excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 28754886). Finally, it has been noted among multiple Chinese PKU patients with BH4 deficiency excluded by urinary pterin analysis, including in the homozygous state in a Chinese patient with classic PKU (plasma Phe not noted), in another patient with PKU (phenotype not further specified) in presumed trans with the c.611A>G (p.Ex6-96A>G) variant (Pathogenic by ClinGen PAH VCEP), in presumed trans with the p.V399V variant (Pathogenic by ClinGen PAH VCEP) in another Chinese patient with mild PKU, and in presumed trans with the p.Y356* variant (Pathogenic by ClinGen PAH VCEP) (PMID: 30050108). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.889) (PP3). Classification: Pathogenic Supporting Criteria: PM3_VeryStrong; PM2_supporting; PP4_Moderate; PP3