ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1033G>T (p.Ala345Ser) (rs62516062)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000088715 SCV000239081 pathogenic not provided 2018-08-31 criteria provided, single submitter clinical testing The A345S missense variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The A345S variant has been reported previously in anindividual with mild phenylketonuria (PKU) who was heterozygous for A345S and a severe PAHpathogenic variant, and in this individual's mother with hyperphenylalaninemia (HPA) who washeterozygous for A345S and another missense variant in PAH (Ho et al., 2014). It is unknown ifA345S is responsive to tetrahydrobiopterin (BH4) therapy.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000088715 SCV000281653 pathogenic not provided 2014-12-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586982 SCV000696422 pathogenic Phenylketonuria 2017-03-30 criteria provided, single submitter clinical testing Variant summary: The PAH c.1033G>T (p.Ala345Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the C-terminal aromatic amino acid hydroxylase domain (InterPro) and 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0000166 (2/120330 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). Published studies have identified the variant in numerous with patients with PKU and/or HPA, including reports of this variant in compound heterozygosity with other pathogenic/likely pathogenic variants and evidence that the variant cosegregates with disease in a family (Ho_JIMDReports_2013). Additionally, one publication that analyzed the crystal structure of PAH protein reported that the variant of interest is one of "three residues in the active site that are located near the (putative) location of substrate binding or in the region near the catalytic iron" sites, suggesting the variant likely disrupts the critical functions of the protein (Erlandsen_Pediatrics_2003). There are no published in vitro functional studies for the variant; however calculation of the energetic impact (G) by structural modeling shows that this variant leads to lower impact on PAH stability and predicted to cause mild hyperphenylalaninemia (Pey_2007). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Counsyl RCV000586982 SCV000789292 likely pathogenic Phenylketonuria 2017-01-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000586982 SCV000893269 pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088715 SCV000119295 not provided not provided no assertion provided not provided

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