ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.965C>G (p.Ala322Gly) (rs62514958)

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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 RCV000675108 SCV001146699 likely pathogenic Phenylketonuria 2019-09-27 reviewed by expert panel curation The c.965C>G (p.Ala322Gly) variant in PAH has been reported in 4 individuals with mild hyperphenylalaninemia (BH4 deficiency not excluded). (PP4; PMID: 12501224). This variant has an allele frequency higher than the PAH VCEP PM2 threshold (MAF=0.00044). This variant was detected with p.R408W in 3 individuals (Pathogenic in ClinVar) and with p.R252W in 1 individual (PM3_strong; PMID: 12501224). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM3-strong, PP3.
Counsyl RCV000675108 SCV000800656 uncertain significance Phenylketonuria 2018-01-23 criteria provided, single submitter clinical testing
Invitae RCV000675108 SCV000834485 pathogenic Phenylketonuria 2019-02-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 322 of the PAH protein (p.Ala322Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs62514958, ExAC 0.006%). This variant has been reported on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with HPA (PMID: 1301200) and in combination with another PAH variant in several individuals affected with PKU, MHP, or non-PKU HPA (PMID: 27469133, 21871829, 10234516, 1301200). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 616). Experimental studies have shown that this missense change causes a mild reduction in PAH enzymatic activity in vitro (PMID: 9450897, 1301200). A different missense substitution at this codon (p.Ala322Val) has been reported in combination with another PAH variant in an individual affected with PKU (PMID: 22526846). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000647 SCV000020797 pathogenic Mild non-PKU hyperphenylalanemia 1992-01-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089177 SCV000119792 not provided not provided no assertion provided not provided

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