ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1162G>C (p.Val388Leu)

dbSNP: rs62516101
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001269277 SCV001448617 pathogenic Phenylketonuria 2020-10-16 reviewed by expert panel curation This c.1162G>C (p.Val388Leu) variant in PAH was reported in 3 patients with PAH deficiency (PMID: 27121329, 31623983) detected with the likely pathogenic variant p.Pro281Leu and the pathogenic variant p.Arg252Trp. DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 27121329). This variant is a novel missense change at an amino acid residue where a different missense change p.Val388Met determined to be pathogenic has been seen before. This variant is present in Dominican populations at a minor allele frequency of 0.00052 (PAGE study). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_moderate.
GeneDx RCV000088775 SCV000582978 likely pathogenic not provided 2016-03-17 criteria provided, single submitter clinical testing The V388L variant has been reported in a Korean patient with PKU who also harbored a second missense variant in the PAH gene (Park et al. 1998). The V388L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species, and a missense variant at the same position (V388M) has been reported in the Human Gene Mutation Database in association with PKU (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, the V388L variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088775 SCV000119360 not provided not provided no assertion provided not provided

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