ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1340C>A (p.Ala447Asp) (rs76542238)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000088834 SCV000577217 pathogenic not provided 2017-04-06 criteria provided, single submitter clinical testing The A447D variant in the PAH gene has been reported as a pathogenic variant in the PAHConsortium Database. The A447D variant has been previously reported in two individuals withclassical phenylketonuria (PKU). These individuals harbored another PAH variant in trans (Guldberg etal., 1996). Functional analysis revealed that A447D is associated with 25% residual enzyme activitycompared to wild type (Hufton et al., 1998). The A447D variant is classified as not responsive totetrahydrobiopterin (BH4) therapy (Sarkissian et al., 2012). The A447D variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ inpolarity, charge, size and/or other properties. This substitution occurs at a position that is conservedacross species, and in silico analysis predicts this variant is probably damaging to the proteinstructure/function. This variant is located within the last 24 amino acids of the C-terminus. When thisis removed, the activity of PAH is abrogated (Hufton et al., 1998). In summary, we interpret A447Das pathogenic.
Invitae RCV000632880 SCV000754081 pathogenic Phenylketonuria 2017-11-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 447 of the PAH protein (p.Ala447Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs76542238, ExAC 0.002%). This variant has been reported in combination with another PAH variant in several individuals affected with phenylketonuria (PMID: 8659548, 23430918, Invitae) and it has also been reported in several individuals affected with hyperphenylalaninaemia or phenylketonuria with no second allele reported (PMID: 12173030, 10429004). ClinVar contains an entry for this variant (Variation ID: 102595). Experimental studies have shown that this missense change causes a reduction in PAH enzyme activity and affects the assembly of the subunits of the PAH enzyme (PMID: 9540801). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000632880 SCV000919914 pathogenic Phenylketonuria 2019-09-17 criteria provided, single submitter clinical testing Variant summary: PAH c.1340C>A (p.Ala447Asp) results in a non-conservative amino acid change located in the oligomerization domain (Hufton_1998). 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 8e-06 in 251166 control chromosomes (gnomAD). The variant, c.1340C>A, has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Guldberg_1996, O'Donnell_2002). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and reported that the variant decreases subunit assembly, resulting in compromised enzyme activity (Hufton_1998). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088834 SCV000119426 not provided not provided no assertion provided not provided

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