ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.493G>C (p.Ala165Pro)

dbSNP: rs199475626
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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 RCV000672775 SCV001146732 uncertain significance Phenylketonuria 2019-04-07 reviewed by expert panel curation The c.493G>C (p.Ala165Pro) variant in PAH has been reported in a French patient with mild PKU with p.Glu390Gly, but parents were not tested (PP4; PMID: 26666653) This variant is absent from 1000G and ESP, and has extremely low frequency in ExAC/gnomAD: MAF 0.00001 (PM2). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.956 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3.
Counsyl RCV000672775 SCV000797914 uncertain significance Phenylketonuria 2018-02-14 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000672775 SCV001586744 pathogenic Phenylketonuria 2021-12-24 criteria provided, single submitter clinical testing This variant is present in population databases (rs199475626, gnomAD 0.0009%). This missense change has been observed in individual(s) with phenylkeonuria (PMID: 26666653). ClinVar contains an entry for this variant (Variation ID: 102701). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. This variant disrupts the p.Ala165 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26666653; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 165 of the PAH protein (p.Ala165Pro).
3billion, Medical Genetics RCV000672775 SCV002058464 likely pathogenic Phenylketonuria 2022-01-03 criteria provided, single submitter clinical testing The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102700,VCV000805818, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.956, 3CNET: 0.997, PP3_P). A missense variant is a common mechanism associated with Phenylketonuria (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088949 SCV000119550 not provided not provided no assertion provided not provided

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