ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.442G>A (p.Gly148Ser) (rs80297647)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001053534 SCV001250531 likely pathogenic Phenylketonuria 2019-12-22 reviewed by expert panel curation The PAH variant c.442G>A (p.Gly148Ser) has been reported in three individuals with PHA deficiency (Phe levels >120 microM). One patient from the Northeastern region of the US, (PMID: 8659548)(PMID:10429004), one patient from Europe (PMID: 10679941), and one patient from the Campania Region in Southern Italy with mild PKU (Phe between 600 and 1200 microM) (PMID: 17096675). The variant c.442G>A (p.Gly148Ser) was document with the pathogenic variant c.194T>C (p.Ile65Thr)(ClinVar ID: 636), and with the pathogenic variant c.473G>A (p.Arg158Gln)(ClinVar ID: 587) (PMID: 8535445). According to gnomAD, this variant is present at a low allele frequency in population databases, with the highest reported frequency in the African population (0.00006). In silico modeling predicts that this missense variant is damaging by SIFT, probably damaging by Polyphen 2 and disease causing by Mutation Taster. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, and PP4 .
Invitae RCV001053534 SCV001217801 uncertain significance Phenylketonuria 2019-11-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 148 of the PAH protein (p.Gly148Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with phenylketonuria (PMID: 8535445, 7726156, 9012412, 10679941). ClinVar contains an entry for this variant (Variation ID: 102680). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088928 SCV000119527 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.