ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1123C>G (p.Gln375Glu)

gnomAD frequency: 0.00003  dbSNP: rs184148104
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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 RCV000817803 SCV002032216 likely pathogenic Phenylketonuria 2020-06-22 reviewed by expert panel curation The c.1123C>G (p.Gln375Glu) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID:26503515). It was detected in trans with pathogenic variants: p.Arg243Gln; p.Arg408Trp; EX6-96A＞G (PMID: 28982351); c.977G>A (p.W326*); p.R413P (PMID: 3005010). This variant has an allele frequency in gnomAD (MAF=0.0003808) that is above the PAH VCEP cutoff for pathogenicity (0.0002). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_very-strong.
Labcorp Genetics (formerly Invitae), Labcorp RCV000817803 SCV000958386 pathogenic Phenylketonuria 2024-02-26 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 375 of the PAH protein (p.Gln375Glu). This variant is present in population databases (rs184148104, gnomAD 0.05%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 28982351, 29499199). ClinVar contains an entry for this variant (Variation ID: 660581). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc. RCV000817803 SCV002060091 likely pathogenic Phenylketonuria 2021-11-09 criteria provided, single submitter clinical testing NM_000277.1(PAH):c.1123C>G(Q375E) is a missense variant classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. The Q375E variant can be associated with any form of this disease. Q375E has been observed in cases with relevant disease (PMID: 30050108, 29499199, 28982351, 30747360, 33803550, 31737040, Chen_2015_(no PMID; article)). Functional assessments of this variant are not available in the literature. Q375E has been observed in population frequency databases (gnomAD: EAS 0.04%). In summary, NM_000277.1(PAH):c.1123C>G(Q375E) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000817803 SCV003922609 likely pathogenic Phenylketonuria 2023-03-30 criteria provided, single submitter clinical testing Variant summary: PAH c.1123C>G (p.Gln375Glu) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251286 control chromosomes. c.1123C>G has been reported in the literature as biallelic compound heterozygous genotypes in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, PKU) of varying severity from mild hyperphenylalaninaemia (MHP) to classic PKU (example, Liu_2017, Li_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000817803 SCV004201352 likely pathogenic Phenylketonuria 2024-03-25 criteria provided, single submitter clinical testing

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