Submissions for variant NM_000277.3(PAH):c.932T>C (p.Leu311Pro)

gnomAD frequency: 0.00001  dbSNP: rs62642936

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000608	SCV001370846	pathogenic	Phenylketonuria	2020-02-22	reviewed by expert panel	curation	The c.932T>C (p.Leu311Pro) variant in PAH has been reported in multiple individuals with PAH deficiency BH4 defect excluded). (PMID: 9634518). This variant has an extremely low allele frequency in gnomAD. This variant has enzyme activity <1% in both standard cDNA and intinic systems. This variant was detected with pathogenic variants I65T (PMID: 23842451) p.Y386C (PMID: 22841515) p.R261Q (PMID: 21871829) c.842+5G>A (PMID: 19609714) p.Gly257Asp (PMID: 26666653) (parental analysis not reported) and in trans with pathogenic variant c.842+1G>A (PMID: 27121329) >2 points. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PP4_Moderate, PS3_supporting, PM2, PP3.
Counsyl	RCV000000608	SCV000220931	likely pathogenic	Phenylketonuria	2014-12-02	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000608	SCV001339028	pathogenic	Phenylketonuria	2020-03-13	criteria provided, single submitter	clinical testing	Variant summary: PAH c.932T>C (p.Leu311Pro) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251288 control chromosomes (gnomAD). c.932T>C has been reported in the literature in multiple individuals in affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Rivera_2000, Jeannesson-Thivisol_2015, Aldamiz-Echevarria_2016). These data indicate that the variant is very likely to be associated with disease. At least two in vitro studies report this variant has an impact on protein function and results in <10% of normal PAH activity. 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.
Invitae	RCV000000608	SCV001583222	pathogenic	Phenylketonuria	2023-05-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects PAH function (PMID: 12655546, 17935162, 30037505). 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 expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 578). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 2615649, 2840952, 9359039, 9634518, 10394930, 21871829). This variant is present in population databases (rs62642936, gnomAD 0.005%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 311 of the PAH protein (p.Leu311Pro).
Revvity Omics, Revvity	RCV000000608	SCV002016499	pathogenic	Phenylketonuria	2020-07-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000000608	SCV004201978	pathogenic	Phenylketonuria	2022-05-25	criteria provided, single submitter	clinical testing
OMIM	RCV000000608	SCV000020758	pathogenic	Phenylketonuria	1988-04-19	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089164	SCV000119779	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000000608	SCV002088637	pathogenic	Phenylketonuria	2021-07-20	no assertion criteria provided	clinical testing