Submissions for variant NM_000277.3(PAH):c.1097C>A (p.Pro366His)

dbSNP: rs62516098

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000672118	SCV001762316	likely pathogenic	Phenylketonuria	2020-08-14	reviewed by expert panel	curation	The c.1097C>A (p.Pro366His) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 8268925). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: p.R158Q (PMID: 8830172); c.165delT (p.F55fs, PMID: 19292873); c.1066-11G>A (PMID: 22841515); p.P281L (PMID: 21147011). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3.
Counsyl	RCV000672118	SCV000797184	likely pathogenic	Phenylketonuria	2018-01-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672118	SCV000917924	pathogenic	Phenylketonuria	2018-05-21	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1097C>A (p.Pro366His) results in a non-conservative amino acid change located in the catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 121284 control chromosomes. c.1097C>A has been reported in the literature in multiple individuals affected with Hyperphenylalaninemia and mild PKU responsive to BH4. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000672118	SCV001203263	pathogenic	Phenylketonuria	2023-08-03	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 366 of the PAH protein (p.Pro366His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria and hyperphenylalaninemia (PMID: 17096675, 19292873, 19609714, 22841515, 26210745). ClinVar contains an entry for this variant (Variation ID: 102521). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000672118	SCV004209668	pathogenic	Phenylketonuria	2023-05-20	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088754	SCV000119338	not provided	not provided		no assertion provided	not provided