Submissions for variant NM_000277.3(PAH):c.737C>T (p.Ala246Val)

gnomAD frequency: 0.00001  dbSNP: rs199475610

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000673258	SCV002540124	likely pathogenic	Phenylketonuria	2024-09-06	reviewed by expert panel	curation	The c.737C>T (p.Ala246Val) variant in PAH is a missense variant that is predicted damaging by REVEL (REVEL score 0.932) (PP3_Moderate). has been reported in multiple patients with PAH deficiency (BH4 deficiency excluded in one patient) (PMID: 9634518, 10394930, 12655553, 30747360, 32668217), including in one patient in unknown phase with the known pathogenic variant p.Arg408Trp (ClinVar ID: 577) (PM3_Supporting). The maximum population allele frequency in gnomAD v2.1.1 is 0.000008808, under the 0.0002 cutoff for use of PM2 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: PM2_Supporting, PM3_Supporting, PP3_Moderate, PP4_Moderate.
Counsyl	RCV000673258	SCV000798440	uncertain significance	Phenylketonuria	2018-03-05	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089068	SCV000119674	not provided	not provided		no assertion provided	not provided