Submissions for variant NM_000277.3(PAH):c.1162G>A (p.Val388Met)

gnomAD frequency: 0.00005  dbSNP: rs62516101

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000650	SCV000852098	pathogenic	Phenylketonuria	2018-08-05	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: Extremely low in ExAC and 1000 genomes (PMID:9860305); PS3: PAH activity in COS cell expression system 15% (PMID:9860305); PM3: Compound het with severe mutation (PMID:9860305); PP3: ; PP4: Reported in patient with classic PKU (PMID:9860305). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PS3, PM3, PP3, PP4).
Eurofins Ntd Llc (ga)	RCV000088774	SCV000203178	pathogenic	not provided	2017-01-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000650	SCV000629174	pathogenic	Phenylketonuria	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 388 of the PAH protein (p.Val388Met). This variant is present in population databases (rs62516101, gnomAD 0.05%). This missense change has been observed in individual(s) with PKU (PMID: 7581408, 12655544, 17935162, 23500595, 23932990; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Spain and Portugal ancestry (PMID: 7581408, 7668259, 12655544, 17935162, 23500595, 23932990; internal data). ClinVar contains an entry for this variant (Variation ID: 619). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 19036622, 21953985). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000650	SCV001361066	pathogenic	Phenylketonuria	2019-06-21	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1162G>A (p.Val388Met) results in a conservative amino acid change located in the aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251286 control chromosomes, predominantly at a frequency of 0.00041 within the Latino subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.00041 vs 0.0079), allowing no conclusion about variant significance. The variant, c.1162G>A, has been reported in the literature in homozygous or compound heterozygous state in multiple individuals affected with mild or classic PKU (Dobrowolski_2011, Danecka_2015). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated variant proteins to have considerably reduced PAH activity compared to wild type (Dobrowolski_2011, Danecka_2015). Four submitters including one expert panel (ClinGen PAH Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
3billion, Medical Genetics	RCV000000650	SCV002318725	pathogenic	Phenylketonuria	2022-03-22	criteria provided, single submitter	clinical testing	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000619, PMID:8406445). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 9860305). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 9860305). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102541,VCV000120260, PMID:26666653,9452061). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.862>=0.6, 3CNET: 0.99>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000992). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV000000650	SCV002809757	pathogenic	Phenylketonuria	2021-08-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000000650	SCV003822304	pathogenic	Phenylketonuria	2022-09-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000000650	SCV004201336	pathogenic	Phenylketonuria	2024-02-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000088774	SCV004222240	pathogenic	not provided	2021-04-12	criteria provided, single submitter	clinical testing	Functional studies in the published literature indicate the variant exhibited 12-43% of normal enzyme activity (PMID: 7668259 (1995), 25596310 (2015), 24401910 (2014), 10767175 (2000), and is associated with a milder phenotype of PKU responsive to BH4 (PMID: 16504182 (2006), 17935162 (2008)). Based on the available information, the variant is classified as pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000000650	SCV005373879	pathogenic	Phenylketonuria	2024-09-22	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000000650	SCV005416838	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3+PM3_VeryStrong+PP4
OMIM	RCV000000650	SCV000020800	pathogenic	Phenylketonuria	1995-08-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088774	SCV000119359	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000000650	SCV000485296	pathogenic	Phenylketonuria	2016-09-09	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000000650	SCV001463118	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing