Submissions for variant NM_000277.3(PAH):c.1181A>C (p.Asp394Ala)

dbSNP: rs62516102

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001789755	SCV002032189	likely pathogenic	Phenylketonuria	2020-08-17	reviewed by expert panel	curation	The c.1181A>C (p.Asp394Ala) variant in PAH has been reported in multiple Sicilian individuals with PAH deficiency (BH4 deficiency excluded, PMID: 8268925). This variant is absent in population databases. This variant was detected with pathogenic variants: p.R261Q (PMID: 8830172); IVS4+5G>T (PMID: 21837404). 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, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001789755	SCV002235715	pathogenic	Phenylketonuria	2022-11-09	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 394 of the PAH protein (p.Asp394Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hyperphenylalaninemia (PMID: 8268925, 8830172, 9634518, 32668217). ClinVar contains an entry for this variant (Variation ID: 102546). 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. This variant disrupts the p.Asp394 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8889590, 26666653, 31355225). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323399	SCV004030149	uncertain significance	not specified	2023-07-24	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1181A>C (p.Asp394Ala) results in a non-conservative amino acid change located in the Eukaryotic phenylalanine-4-hydroxylase, catalytic domain (IPR041912) 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 251306 control chromosomes (gnomAD). c.1181A>C has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (e.g. Guldberg_1993, Romano_1996, Amorini_2012, Hillert_2020)). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21837404, 8268925, 32668217, 8830172). Two ClinVar submitters have assessed the variant since 2014: one submitter classified the variant as pathogenic, and another (an expert panel) classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088780	SCV000119367	not provided	not provided		no assertion provided	not provided