ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.691T>C (p.Ser231Pro)

dbSNP: rs5030845
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000190611 SCV000245645 pathogenic Phenylketonuria 2014-09-24 criteria provided, single submitter clinical testing The p.Ser231Pro variant has been reported at least seven individuals with phenylketonuria (PKU) in the homozygous or compound heterozygous state (Effat 1999, Daniele 2008, Hamzelhoei 2012, Ajami 2013), and was not identified in large population studies. In vitro functional assays suggest complete loss of enzymatic activity (Dianzani 1995). In summary, this variant meets our criteria to be classified as pathogenic for PKU in an autosomal recessive manner for PKU based upon presence in affected individuals, absence from controls, and functional evidence (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medicine/).
Counsyl RCV000190611 SCV000796824 pathogenic Phenylketonuria 2018-01-03 criteria provided, single submitter clinical testing
Invitae RCV000190611 SCV001223743 pathogenic Phenylketonuria 2023-01-22 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PAH function (PMID: 8535444, 10394930). 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. ClinVar contains an entry for this variant (Variation ID: 102786). This missense change has been observed in individual(s) with phenylketonuria (PMID: 18346471, 27682710). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 231 of the PAH protein (p.Ser231Pro).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000190611 SCV002015118 pathogenic Phenylketonuria 2021-10-29 criteria provided, single submitter clinical testing Variant summary: PAH c.691T>C (p.Ser231Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251314 control chromosomes. c.691T>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, e.g. Shirzadeh_2018). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000190611 SCV004201386 pathogenic Phenylketonuria 2023-10-03 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089037 SCV000119642 not provided not provided no assertion provided not provided
Natera, Inc. RCV000190611 SCV001453116 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing

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