Submissions for variant NM_000277.3(PAH):c.926C>T (p.Ala309Val)

gnomAD frequency: 0.00001  dbSNP: rs62642935

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000150082	SCV000852158	pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: Low frequency. 1.0e-5; PP3: All databases agree on damaging effect. REVEL=0.921; PS3: Enzyme activity = 30% (Ho, 2008) (PMID:18590700); PM3: Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T (PMID:26666653); PP4: Single patient with classic PKU (>1200umol/L), BH4 defect not excluded (PMID:26666653). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4).
Eurofins Ntd Llc (ga)	RCV000078538	SCV000110394	pathogenic	not provided	2012-08-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000078538	SCV000581842	pathogenic	not provided	2023-10-05	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as responsive to tetrahydrobiopterin (BH4) therapy (Zurflh et al., 2008; Aldmiz- Echevarra et al., 2016); This variant is associated with the following publications: (PMID: 23559577, 16051511, 8830172, 16091306, 10679941, 15459954, 8533759, 25087612, 21953985, 8268925, 16504182, 15464430, 10234516, 26990548, 32668217, 31589614, 32778825, 12655546, 17935162, 33465300, 30037505, 27121329)
Invitae	RCV000150082	SCV000629226	pathogenic	Phenylketonuria	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 309 of the PAH protein (p.Ala309Val). This variant is present in population databases (rs62642935, gnomAD 0.003%). This missense change has been observed in individual(s) with PKU (PMID: 12655546, 21871829, 26666653, 27121329). ClinVar contains an entry for this variant (Variation ID: 92753). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 12655546, 15459954, 16504182). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150082	SCV001774587	pathogenic	Phenylketonuria	2021-07-19	criteria provided, single submitter	clinical testing	Variant summary: PAH c.926C>T (p.Ala309Val) 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 1.6e-05 in 251284 control chromosomes. c.926C>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Hennermann_2000, Ley_2003, Dobrowolski_2007, Rivera_2011, Aldamiz-Echevarria_2016). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced enzyme activity, folding defect causing reduced stability and accelarated degradation (example, Ley_2003, Aldamiz-Echevarria_2016). Multiple clinical diagnostic laboratories and an expert panel (ClinGen PAH Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=4)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000150082	SCV004201378	pathogenic	Phenylketonuria	2024-03-27	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078538	SCV000119775	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000150082	SCV000487182	likely pathogenic	Phenylketonuria	2016-10-20	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000150082	SCV001463130	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing