ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.776C>T (p.Ala259Val) (rs118203921)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000000633 SCV000486832 likely pathogenic Phenylketonuria 2016-08-23 criteria provided, single submitter clinical testing
Invitae RCV000000633 SCV000951041 pathogenic Phenylketonuria 2019-07-12 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 259 of the PAH protein (p.Ala259Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs118203921, ExAC 0.01%). This variant has been observed to be homozygous or in combination with another PAH variant in individuals affected with phenylketonuria (PMID: 26666653, 18299955, 2035532). ClinVar contains an entry for this variant (Variation ID: 602). Experimental studies have shown that this missense change disrupts protein folding, assembly of the active enzyme complex and abrogates PAH enzyme activity (PMID: 9799096, 8304187, 10479481). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000633 SCV000020783 pathogenic Phenylketonuria 1991-06-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089089 SCV000119695 not provided not provided no assertion provided not provided

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