Submissions for variant NM_000277.3(PAH):c.1180G>C (p.Asp394His)

dbSNP: rs62516142

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000714571	SCV002032190	likely pathogenic	Phenylketonuria	2020-08-17	reviewed by expert panel	curation	The c.1180G>C (p.Asp394His) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 8889590, 21147011, 31355225 ). This variant is absent in population databases. This variant was detected with pathogenic variants IVS10-11G>A (PMID: 8889590); IVS11nt1g>c (IVS11+1G>C, PMID: 10947211). 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000714571	SCV000845274	likely pathogenic	Phenylketonuria	2018-08-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000714571	SCV004039243	pathogenic	Phenylketonuria	2023-08-24	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1180G>C (p.Asp394His) results in a non-conservative amino acid change in 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.1180G>C has been reported in the literature in a homozygous and multiple compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria), with phenotypes ranging from mild hyperphenylalaninemia to classic-phenylketonuria (e.g. Guldberg_1996, Dobrowolski_2011, Su_2019, Bik-Multanowski_2022, Hillert_2020); all reported compound heterozygous individuals carried a pathogenic second variant. These data indicate that the variant is very likely to 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: 8889590, 21147011, 31355225, 35176108, 32668217). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000714571	SCV004294261	pathogenic	Phenylketonuria	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 394 of the PAH protein (p.Asp394His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 8889590, 31355225, 32668217). 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: 102545). 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%. 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: 8268925, 8830172, 9634518, 32668217). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000088779	SCV004701845	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PAH: PM3:Very Strong, PM2, PP4
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088779	SCV000119366	not provided	not provided		no assertion provided	not provided