Submissions for variant NM_000277.3(PAH):c.1340C>A (p.Ala447Asp)

gnomAD frequency: 0.00001  dbSNP: rs76542238

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000088834	SCV000577217	pathogenic	not provided	2022-07-21	criteria provided, single submitter	clinical testing	Reported as not associated with tetrahydrobiopterin (BH4) therapy responsiveness (Sarkissian et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10980574, 12655553, 23430918, 8659548, 10429004, 9540801, 27535533, 32668217, 7893121, 12173030)
Invitae	RCV000632880	SCV000754081	pathogenic	Phenylketonuria	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 447 of the PAH protein (p.Ala447Asp). This variant is present in population databases (rs76542238, gnomAD 0.002%). This missense change has been observed in individual(s) with hyperphenylalaninaemia or phenylketonuria (PMID: 10429004, 12173030). ClinVar contains an entry for this variant (Variation ID: 102595). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 9540801). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000632880	SCV000919914	pathogenic	Phenylketonuria	2019-09-17	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1340C>A (p.Ala447Asp) results in a non-conservative amino acid change located in the oligomerization domain (Hufton_1998). 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 8e-06 in 251166 control chromosomes (gnomAD). The variant, c.1340C>A, has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Guldberg_1996, O'Donnell_2002). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and reported that the variant decreases subunit assembly, resulting in compromised enzyme activity (Hufton_1998). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003407485	SCV004104649	pathogenic	PAH-related condition	2023-08-28	criteria provided, single submitter	clinical testing	The PAH c.1340C>A variant is predicted to result in the amino acid substitution p.Ala447Asp. This variant has been reported in multiple individuals with phenylalanine hydroxylase deficiency (Guldberg et al. 1996. PubMed ID: 8659548; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). In an experimental study, substitution of the homologous amino acid in the rat PAH protein [A(447)D] was reported to affect enzyme function (Hufton et al. 1998. PubMed ID: 9540801). An alternate substitution of the same amino acid (p.Ala447Pro) has also been reported in affected individuals (for example, see Table S3 in Hillert et al. 2020. PubMed ID: 32668217). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-103232972-G-T). In summary, this variant is interpreted as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000088834	SCV004184264	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	PAH: PM3:Very Strong, PM2, PM5, PS3:Supporting
Baylor Genetics	RCV000632880	SCV004201316	pathogenic	Phenylketonuria	2023-10-31	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088834	SCV000119426	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000632880	SCV002088615	pathogenic	Phenylketonuria	2020-09-23	no assertion criteria provided	clinical testing