ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.283A>T (p.Ile95Phe) (rs62508682)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000088890 SCV000329447 pathogenic not provided 2016-08-11 criteria provided, single submitter clinical testing The I95F variant is also located in the regulatory domain of the phenylalanine hydroxylase enzyme and has previously been reported in unrelated individuals with mild PKU (Carluccio et al., 2013; Zekanowski et al. 1999; Bercovich et al., 2008).
Fulgent Genetics,Fulgent Genetics RCV000763292 SCV000893953 likely pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000763292 SCV000919908 pathogenic Phenylketonuria 2020-11-02 criteria provided, single submitter clinical testing Variant summary: PAH c.283A>T (p.Ile95Phe) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Three 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 251440 control chromosomes (gnomAD). c.283A>T has been reported in the literature in individuals (compound heterozygous) affected with mild and moderate Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Bercovich_2008, Zekanowski_1999, Rajabi_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000763292 SCV001380546 likely pathogenic Phenylketonuria 2020-09-16 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 95 of the PAH protein (p.Ile95Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is present in population databases (rs62508682, ExAC 0.004%). This variant has been observed in combination with another PAH variant in several individuals affected with phenylketonuria (PMID: 10495930, 18299955). ClinVar contains an entry for this variant (Variation ID: 102645). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088890 SCV000119487 not provided not provided no assertion provided not provided

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