ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1074A>T (p.Leu358Phe) (rs376480977)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672872 SCV000798020 uncertain significance Phenylketonuria 2018-02-22 criteria provided, single submitter clinical testing
Invitae RCV000672872 SCV000940771 likely pathogenic Phenylketonuria 2018-07-30 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 358 of the PAH protein (p.Leu358Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs376480977, ExAC 0.003%). This variant has been observed in combination with another PAH variant in several individuals affected with hyperphenylalaninemia (PMID: 23357515, 23764561, Invitae). Experimental studies have shown that this missense change exhibits reduced enzyme activity (PMID: 28653649). 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.

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