ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.632C>T (p.Pro211Leu) (rs281865443)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000106364 SCV000629204 likely pathogenic Phenylketonuria 2019-09-23 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 211 of the PAH protein (p.Pro211Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (rs281865443, ExAC no frequency). This variant has been reported in an individual affected with classic phenylketonuria and PAH deficiency (PMID: 24350308, Invitae). ClinVar contains an entry for this variant (Variation ID: 120283). 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. A different missense substitution at this codon (pPro211Thr) has been determined to be pathogenic (PMID: 17935162, 23500595, 8268925, 16198137, 9429153, 11708866). This suggests that the proline residue is critical for PAH protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change that has been reported in affected individuals, it is predicted to affect protein function and there is a different pathogenic missense change at the same codon. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl RCV000106364 SCV000798689 likely pathogenic Phenylketonuria 2018-03-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000106364 SCV001361332 likely pathogenic Phenylketonuria 2019-10-17 criteria provided, single submitter clinical testing Variant summary: PAH c.632C>T (p.Pro211Leu) results in a non-conservative amino acid change in the catalytic domain (IPR041912) of 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 251336 control chromosomes (gnomAD). c.632C>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Gundorova_2016, Bik-Multanowski_2013). These data indicate that the variant may be associated with disease. Two ClinVar submissions (evaluation after 2014) cite the variant as likely pathogenic. In addition, another variant affecting the same codon, P211T, along with variants nearby, N207S, L213P, E214G, have been reported to be associated with PKU. Therefore, suggesting the region is important for protein function. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Inserm U 954, Faculté de Médecine de Nancy RCV000106364 SCV000143864 probable-pathogenic Phenylketonuria no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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