ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1183G>C (p.Ala395Pro) (rs62516103)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000781679 SCV000919911 pathogenic Phenylketonuria 2017-12-07 criteria provided, single submitter clinical testing Variant summary: The PAH c.1183G>C (p.Ala395Pro) variant involves the alteration of a conserved nucleotide located in Catalytic domain (Zurfluh_2008). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 5/246070 control chromosomes at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported in multiple PKU patients and shown to lead to decreased residual activity (Zurfluh_2008, Dobrowolski_2007, Lassker_2002). Taken together, this variant is classified as pathogenic.
Invitae RCV000781679 SCV000948126 pathogenic Phenylketonuria 2019-05-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 395 of the PAH protein (p.Ala395Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs62516103, ExAC 0.003%). This variant has been observed in several individuals with classic PKU (PMID: 11999982, 7726156, 22841515, 17502162). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102547). This variant has been reported to affect PAH protein function (PMID: 11161839). For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088781 SCV000119368 not provided not provided no assertion provided not provided

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