ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1136T>C (p.Val379Ala)

gnomAD frequency: 0.00002  dbSNP: rs746203167
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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 RCV002260485 SCV002540117 uncertain significance Phenylketonuria 2020-05-08 reviewed by expert panel curation The c.1136T>C (p.Val379Ala) PAH variant has been reported in at least two mild HPA probrands with exclusion of BH4 deficiency (PMID: 21307867). This variant is found at an extremely low frequency (0.0001737) in the gnomAD Latino population. It is a missense variant predicted deleterious by SIFT (damaging) and MutationTaster (disease causing), with a REVEL score of 0.796. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4_moderate.
Baylor Genetics RCV002260485 SCV004209636 likely pathogenic Phenylketonuria 2024-02-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003478955 SCV004222239 uncertain significance not provided 2022-10-13 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.00017 (6/34544 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Hyperphenylalaninenemia (HPA) (PMID: 33803550 (2021) and 21307867 (2011)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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