ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.601C>T (p.His201Tyr) (rs62517205)

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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 RCV000509208 SCV001250523 likely pathogenic Phenylketonuria 2019-11-10 reviewed by expert panel curation The c.601C>T (p.His201Tyr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 16198137). This variant is at a ow frequency in controls (3.964e-6 in gnomAD; PM2). This variant was detected with known pathogenic variants IVS10nt546 (PMID: 9521426) and R158Q (PMID: 16198137; PM3_strong). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong.
Invitae RCV000509208 SCV000629203 pathogenic Phenylketonuria 2018-09-25 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 201 of the PAH protein (p.His201Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals diagnosed with hyperphenylalaninemia co-occurring with known pathogenic PAH variants (PMID: 9521426, 10598814, 16198137, 23792259). ClinVar contains an entry for this variant (Variation ID: 102752). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000588479 SCV000696446 pathogenic Hyperphenylalaninemia, non-pku 2017-04-13 criteria provided, single submitter clinical testing Variant summary: The PAH c.601C>T (p.His201Tyr) variant located in the Aromatic amino acid hydroxylase, C-terminal (via InterPro) involves the alteration of a conserved nucleotide and 3/5 in silico tools predict a damaging outcome. Reblova_2013 indicates that the His201 plays a key role in forming a H-bond needed for stablization. This variant is absent in 121300 control chromosomes (ExAC). Multiple publications have cited the variant in affected compound heterozygote individuals, predominantly from Italy, with a mild HPA. Taken together, the variant of interest has been classified as "pathogenic."
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089001 SCV000119605 not provided not provided no assertion provided not provided
Counsyl RCV000509208 SCV001132448 likely pathogenic Phenylketonuria 2017-03-15 no assertion criteria provided clinical testing

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