ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.631C>A (p.Pro211Thr) (rs62514931)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411219 SCV000485613 likely pathogenic Phenylketonuria 2016-01-13 criteria provided, single submitter clinical testing
Invitae RCV000411219 SCV000947663 pathogenic Phenylketonuria 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 211 of the PAH protein (p.Pro211Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with PAH-related conditions (PMID: 17935162, 23500595, 8268925, 16198137, 9429153, 11708866). ClinVar contains an entry for this variant (Variation ID: 102766). Experimental studies have shown that this missense change has a deleterious effect on protein function (PMID: 11708866, 21953985). This variant disrupts the p.Pro211 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 24350308, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001192748 SCV001361069 pathogenic BH4-deficient hyperphenylalaninemia A 2019-09-26 criteria provided, single submitter clinical testing Variant summary: PAH c.631C>A (p.Pro211Thr) results in a non-conservative amino acid change located in the catalytic domain (IPR041912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251336 control chromosomes (gnomAD). c.631C>A has been reported in the literature in multiple individuals (both homozygous and compound heterozygous state) affected with Hyperphenylalaninemia (Guldberg_1993, Couce_2013, Hennermann_2005). These data indicate that the variant is very likely to be associated with disease. Many reports indicate that patients harboring this variant are responsive to tetrahydrobiopterin (BH4) therapy. Anjema_2013 associates this variant with true BH4 responsiveness. Several publications report experimental evidence evaluating an impact on protein function. In most of these functional experiments, variant of interest had a mild reduction in activity compared to the wild type and therefore suggests a subtle effect on protein function. An in vitro assay found this variant to retain 72% of residual activity (Mirisola_2001). Scheller_2019 documented that this variant retains its ability to associate with wild-type PAH, does not form aggregates, and only mildly destabilized in structure. Using sequence conversion and stability methods, Shi_ 2012 suggests a low impact for this variant on protein function. Two ClinVar submitters (evaluation after 2014) cite this variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089016 SCV000119620 not provided not provided no assertion provided not provided

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