Submissions for variant NM_000277.3(PAH):c.161T>C (p.Leu54Ser)

gnomAD frequency: 0.00001  dbSNP: rs199475677

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000669099	SCV001572856	likely pathogenic	Phenylketonuria	2020-07-23	reviewed by expert panel	curation	The c.161T>C (p.Leu54Ser) variant in PAH is a missense variant that is predicted to be deleterious in multiple lines of computational evidence. This variant was reported in a Spanish patient with mild/moderate PKU. A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring the dihydropteridine reductase activity (PMID: 27121329). This variant was detected in trans with pathogenic variant c.912+1G>A. It was found in extremely low frequency in gnomAD (MAF=0.00006). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4 moderate, PM3, and PP3.
Counsyl	RCV000669099	SCV000793804	uncertain significance	Phenylketonuria	2017-11-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586550	SCV005077204	uncertain significance	not specified	2024-04-19	criteria provided, single submitter	clinical testing	Variant summary: PAH c.161T>C (p.Leu54Ser) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251396 control chromosomes. c.161T>C has been reported in the literature as a biallelic compound heterozygous genotye in at-least one individual with moderate Phenylketonuria (PKU) who was also non-responsive on the BH4 loading test (examle, Aldamiz-Echevarria_2016, Hillert_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27121329, 32668217). ClinVar contains an entry for this variant (Variation ID: 102602) with the ClinGen PAH Variant Curation Expert Panel classification as Likely Pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088843	SCV000119436	not provided	not provided		no assertion provided	not provided