ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1033G>T (p.Ala345Ser) (rs62516062)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000586982 SCV001762344 pathogenic Phenylketonuria 2020-06-05 reviewed by expert panel curation The c.1033G>T (p.Ala345Ser) variant in PAH has been reported in multiple individuals with PAH deficiency. (PMID: 24368688, 17502162, 3430918). This variant has an extremely low allele frequency (MAF=0.00008) in gnomAD. It was detected with multiple pathogenic variants: p.R408W (in trans, PMID: 24368688); c.1045T>C, c.194T>C (PMID: 17502162); p.F39del, c.47_48delCT (aka c.43_44CT), c.1066-11G>A (PMID: 23430918); p.E280K, p.L348V, p.Y414C (PMID: 31623983). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VS, PM2, PP3, PP4.
GeneDx RCV000088715 SCV000239081 pathogenic not provided 2021-06-02 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Responsive to tetrahydrobiopterin (BH4) therapy is unclear (Sarkissian et al., 2012); This variant is associated with the following publications: (PMID: 24368688, 25525159, 14654665, 24077912, 27535533, 23430918, 32668217)
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000088715 SCV000281653 pathogenic not provided 2014-12-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586982 SCV000696422 pathogenic Phenylketonuria 2017-03-30 criteria provided, single submitter clinical testing Variant summary: The PAH c.1033G>T (p.Ala345Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the C-terminal aromatic amino acid hydroxylase domain (InterPro) and 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0000166 (2/120330 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). Published studies have identified the variant in numerous with patients with PKU and/or HPA, including reports of this variant in compound heterozygosity with other pathogenic/likely pathogenic variants and evidence that the variant cosegregates with disease in a family (Ho_JIMDReports_2013). Additionally, one publication that analyzed the crystal structure of PAH protein reported that the variant of interest is one of "three residues in the active site that are located near the (putative) location of substrate binding or in the region near the catalytic iron" sites, suggesting the variant likely disrupts the critical functions of the protein (Erlandsen_Pediatrics_2003). There are no published in vitro functional studies for the variant; however calculation of the energetic impact (G) by structural modeling shows that this variant leads to lower impact on PAH stability and predicted to cause mild hyperphenylalaninemia (Pey_2007). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Counsyl RCV000586982 SCV000789292 likely pathogenic Phenylketonuria 2017-01-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000586982 SCV000893269 pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000586982 SCV001235796 pathogenic Phenylketonuria 2020-10-12 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 345 of the PAH protein (p.Ala345Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs62516062, ExAC 0.02%). This variant has been observed in individuals with hyperphenylalaninemia (PMID: 17502162, 23430918, 24368688). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102484). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088715 SCV000119295 not provided not provided no assertion provided not provided
Natera, Inc. RCV000586982 SCV001463125 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.