ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1238G>C (p.Arg413Pro) (rs79931499)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000623 SCV000852136 pathogenic Phenylketonuria 2018-08-05 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PS3: In vitro expression of altered protein in COS cells produces severe decrease of PAH activity (<3%); PM2: Extremely low frequency. ExAC MAF=0.00012; PP4_Moderate: Detected in PKU patients, BH4 deficiency excluded; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.895; PM3: Detected with V388M (pathogenic) in 2 patients (PMID:9860305; PMID:21307867). 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: (PS3, PM2, PP4_Moderate, PP3, PM3).
Counsyl RCV000000623 SCV000486282 pathogenic Phenylketonuria 2016-05-04 criteria provided, single submitter clinical testing
GeneDx RCV000088813 SCV000521188 pathogenic not provided 2016-12-19 criteria provided, single submitter clinical testing The R413P missense variant in the PAH gene has been reported as a pathogenic variant in thePAH Consortium database. The R413P variant is a common variant in the Asian population andhas been associated with a classic phenylketonuria (PKU) phenotype (Wang et al., 1991; Liang etal., 2014). Functional analysis of R413P found that it is associated with significantly reducedenzyme activity and it is classified as responsive to tetrahydrobiopterin (BH4) therapy (Wang etal., 1991; Liang et al., 2014; Zurfluh et al. 2008).
Integrated Genetics/Laboratory Corporation of America RCV000000623 SCV000696433 pathogenic Phenylketonuria 2016-08-05 criteria provided, single submitter clinical testing Variant summary: The PAH c.1238G>C (p.Arg413Pro) variant causes a missense change involving a non-conserved nucleotide with 5/5 in silico tools predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency 1/121344, which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. The variant of interest was found in multiple affected individuals diagnosed with classic PKU via publications and has been indicated that it is predominantly observed in populations of Asian origin. In addition, publications indicated that the patients showed zero PAH activity. In addition, multiple databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic."
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088813 SCV000706081 pathogenic not provided 2017-02-07 criteria provided, single submitter clinical testing
Invitae RCV000000623 SCV001227804 pathogenic Phenylketonuria 2019-09-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 413 of the PAH protein (p.Arg413Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs79931499, ExAC 0.01%). This variant has been observed to be homozygous / in combination with another PAH variant in several individuals affected with PAH-related disease (PMID: 24401910, 27264808). ClinVar contains an entry for this variant (Variation ID: 592). Experimental studies have shown that this missense change impairs PAH enzyme function invitro (PMID: 17935162, 21953985). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000623 SCV000020773 pathogenic Phenylketonuria 1991-03-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088813 SCV000119403 not provided not provided no assertion provided not provided

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.