ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1223G>A (p.Arg408Gln) (rs5030859)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000643 SCV000852159 pathogenic Phenylketonuria 2018-08-05 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM3_Strong: In trans with R408W, IVS4-1G>A, R241C (ClinGen, P) (PMID:1312992; PMID:14722928); PP3: ; PS3: Mutant enzyme activity of 46% in BioPKU (PMID:9860305); PP4_Moderate: ~830 uml/L w/o BH4 deficiency & 823 umol/L, BH4 status unknown (PMID:9860305; PMID:1312992). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM3_Strong, PP3, PS3, PP4_Moderate).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088806 SCV000225501 pathogenic not provided 2017-06-29 criteria provided, single submitter clinical testing
Invitae RCV000000643 SCV000830376 pathogenic Phenylketonuria 2019-12-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 408 of the PAH protein (p.Arg408Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs5030859, ExAC 0.01%). This variant has been observed as homozygous or on the opposite chromosome (in trans) from other pathogenic variants in several individuals affected with PAH-related disease (PMID: 1312992, 24401910, 29317692, 10471838). 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: 612). Experimental studies have shown that this missense change reduces PAH protein stability (PMID: 12655546). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Variants that disrupt the p.Arg408 amino acid residue in PAH have been observed in affected individuals (PMID: 12173030, 2014036, 24401910). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000000643 SCV000919913 pathogenic Phenylketonuria 2018-01-08 criteria provided, single submitter clinical testing Variant summary: The PAH c.1223G>A (p.Arg408Gln) variant located in the Aromatic amino acid hydroxylas, C-terminal domain (InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 13/277144 control chromosomes (gnomAD) at a frequency of 0.0000469, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). Multiple publications have cited the variant in affected compound heterozygous individuals, presenting with a significant decrease in PAH activity. In support of this, there are other variants at the 408 codon that have been reported in patients with PKU (R408L, R408W), suggesting the codon is important for function. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics RCV000000643 SCV001163710 pathogenic Phenylketonuria criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000000643 SCV001194182 pathogenic Phenylketonuria 2019-12-19 criteria provided, single submitter clinical testing NM_000277.1(PAH):c.1223G>A(R408Q) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and can be associated with variant or non-PKU HPA. Sources cited for classification include the following: PMID 14722928, 1312992, 1355066, 1301200, and 8533759. Classification of NM_000277.1(PAH):c.1223G>A(R408Q) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
OMIM RCV000000643 SCV000020793 pathogenic Phenylketonuria 1992-08-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088806 SCV000119396 not provided not provided no assertion provided not provided

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