Submissions for variant NM_000277.3(PAH):c.1184C>G (p.Ala395Gly)

gnomAD frequency: 0.00001  dbSNP: rs62508736

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410586	SCV000485283	likely pathogenic	Phenylketonuria	2016-07-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000410586	SCV000917929	pathogenic	Phenylketonuria	2018-11-16	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1184C>G (p.Ala395Gly) results in a non-conservative amino acid change located in the C-terminal domain, containing the catalytic domain and the coiled-coil C-terminal oligomerization motif (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 7.2e-06 in 276980 control chromosomes (gnomAD). c.1184C>G has been reported in the literature in a homozygous individual affected with mild Hyperphenylalaninemia (MHP) (Bercovich 2008) and multiple compound heterozugous individuals affected with MHP or mild to moderate PKU phenotype (Guttler 1999, Bercovich 2008, Aldamiz-Echevarria 2016). These data indicate that the variant is very likely to be associated with disease; however, in general, patients with mild hyperphenylalaninemia do not require restrictive diet or supplementary treatment unless Phe concentrations reach the clinical threshold. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410586	SCV001220571	pathogenic	Phenylketonuria	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 395 of the PAH protein (p.Ala395Gly). This variant is present in population databases (rs62508736, gnomAD 0.002%). This missense change has been observed in individual(s) with hyperphenylalaninemi and/or phenylketonuria (PMID: 18299955, 24368688, 27121329). ClinVar contains an entry for this variant (Variation ID: 102549). 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%. This variant disrupts the p.Ala395 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7726156, 11161839, 11999982, 17502162, 22841515). 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.
3billion	RCV000410586	SCV002521635	pathogenic	Phenylketonuria	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102549). A different missense change at the same codon (p.Ala395Pro) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102547). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000410586	SCV004209644	pathogenic	Phenylketonuria	2024-02-21	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000410586	SCV004848853	pathogenic	Phenylketonuria	2022-11-03	criteria provided, single submitter	clinical testing	The p.Ala395Gly variant in PAH has been reported in at least 1 homozygous and > 15 compound heterozygous individuals affected with mild Hyperphenylalaninemia or mild to moderate Phenylketonuria (Guldberg 1998 PMID: 9634518, Guttler 1999 PMID: 10429004, Bercovich 2008 PMID: 18299955, Hillert 2020 PMID: 32668217). It has also been reported in ClinVar (Variation ID 102549) and was identified in 1/67986 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Ala395Pro) has been identified in individuals with Phenylketonuria and is classified as pathogenic by clinical laboratories in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperphenylalanemia/phenylkenonuria. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PM3_Very strong, PM5.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088783	SCV000119370	not provided	not provided		no assertion provided	not provided
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000410586	SCV000536786	likely pathogenic	Phenylketonuria	2016-04-28	no assertion criteria provided	research
Natera, Inc.	RCV000410586	SCV002088623	pathogenic	Phenylketonuria	2021-02-17	no assertion criteria provided	clinical testing