ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.199T>C (p.Ser67Pro)

dbSNP: rs5030842
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001260324 SCV004015303 pathogenic Phenylketonuria 2023-03-16 reviewed by expert panel curation The c.199T>C (p.Ser67Pro) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; 8533759; 26351554). This variant has an extremely low allele frequency in ExAC (MAF=0.00002, PM2). This variant was detected in trans with L48S (PMID: 8592329), IVS10-11G>A, R408Q (P), R261Q, R252W (P/LP) PMID: 26351554 (PM3_VS). Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen-2, MutationTaster, REVEL=0.954) (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VS, PM2, PP4_Moderate, PP3.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000088867 SCV000888346 pathogenic not provided 2018-04-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260324 SCV001437249 likely pathogenic Phenylketonuria 2020-09-21 criteria provided, single submitter clinical testing Variant summary: PAH c.199T>C (p.Ser67Pro) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251284 control chromosomes. c.199T>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and has been subsequently cited by others (example, Daniele_2006, Bik-Multanowski_2013, Bagheri_2015). These data indicate that the variant is very likely to be associated with disease. However, to our knowledge, no concrete experimental evidence demonstrating an impact on protein function was ascertained in the context of this classification. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001260324 SCV002246406 pathogenic Phenylketonuria 2024-11-06 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 67 of the PAH protein (p.Ser67Pro). This variant is present in population databases (rs5030842, gnomAD 0.0009%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 12409276, 16198137, 19292873, 19913839). ClinVar contains an entry for this variant (Variation ID: 102625). 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%. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088867 SCV000119463 not provided not provided no assertion provided not provided

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