Submissions for variant NM_000277.3(PAH):c.500A>T (p.Asn167Ile)

dbSNP: rs77554925

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000412232	SCV000852095	likely pathogenic	Phenylketonuria	2018-08-28	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC (MAF=0.00003). Absent from gnomAD, 1000G, ESP; PP4_Moderate: Found in a French patient with HPA and 2 unrelated UK patients. BH4 deficiencies not assessed/reported. Seen in 1 German patient, Cofactor deficiency was excluded by the BH4 test. 1 Spanish patient, a defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring dihydropteridine reductase activity. (PMID:26666653; PMID:9012412; PMID:10679941); PM3_Strong: Patient 664 with genotype N167I/Rl58Q (Pathogenic in ClinVar). Detected with G272X and R408W, known pathogenic variants. (PMID:24368688; PMID:26666653). 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, PP4_Moderate, PM3_Strong).
Eurofins Ntd Llc (ga)	RCV000078523	SCV000110379	uncertain significance	not provided	2017-01-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000412232	SCV000485290	likely pathogenic	Phenylketonuria	2015-12-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412232	SCV000830097	pathogenic	Phenylketonuria	2024-08-02	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 167 of the PAH protein (p.Asn167Ile). This variant is present in population databases (rs77554925, gnomAD 0.007%). This missense change has been observed in individual(s) with PKU or HPA, and carnitine deficiency (PMID: 9452062, 10234516, 22112818, 23430918, 24368688, 26666653; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 92743). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on PAH function (PMID: 12554741). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000412232	SCV001623309	pathogenic	Phenylketonuria	2021-04-20	criteria provided, single submitter	clinical testing	Variant summary: PAH c.500A>T (p.Asn167Ile) 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 3.6e-05 in 251360 control chromosomes. c.500A>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria; e.g. Tyfield_1997, Desviat_1999, Utz_2011, Jeannesson-Thivisol_2015). These data indicate that the variant is very likely to be associated with disease. A functional study investigating the variant effects in E. coli reported that the variant did not appear to significantly alter the kinetic properties of the enzyme, but suggested that it may de-stabilize the secondary structure of the protein, resulting in aggregation (e.g. Carvalho_2003). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance (n=1) and pathogenic/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000412232	SCV002811648	likely pathogenic	Phenylketonuria	2022-03-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000412232	SCV004209573	pathogenic	Phenylketonuria	2023-11-08	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000412232	SCV005086281	pathogenic	Phenylketonuria	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with phenylketonuria (MIM#261600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 -Variant is predicted to result in a missense amino acid change from asparagine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 12 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2 & v3) (highest allele count: 818 heterozygotes, 8 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Biopterin_H domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been regarded likely pathogenic and pathogenic by multiple clinical laboratories in ClinVar including ClinGen expert group. In addition, it has been detected in individuals from different ethnicities with phenylketonuria (PMIDs: 26666653; 30311390, 24368688, 9452062, 10234516, 9012412). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV000078523	SCV005201427	pathogenic	not provided	2021-11-11	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; This variant is associated with the following publications: (PMID: 12554741, 10679941, 10598814, 9634518, 9012412, 9452062, 10234516, 32668217, 26666653)
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078523	SCV000119553	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000412232	SCV002088664	pathogenic	Phenylketonuria	2020-11-23	no assertion criteria provided	clinical testing