ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1256A>G (p.Gln419Arg)

gnomAD frequency: 0.00003  dbSNP: rs752255985
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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 RCV000667759 SCV002032218 pathogenic Phenylketonuria 2020-06-22 reviewed by expert panel curation The c.1256A>G (p.Gln419Arg) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 17096675, PMID: 26503515). This variant has an extremely low allele frequency (MAF=0.00016) in gnomAD. This variant was detected in trans with multiple pathogenic variants: p.S231P (PMID: 18346471); p.Ala434Asp (PMID: 25456745); c.1068C>A (p.Y356*) (PMID: 26322415); p.Arg413Pro; p.Ala403Val; p.Val399=; p.Arg243Gln (2 patients); p.Arg53His (US); EX6-96A＞G (PMID: 28982351). Computational prediction tools are conflicting. PAH-specific ACMG/AMP criteria applied: PM3_ very-strong, PM2, PP4_Moderate.
Counsyl RCV000667759 SCV000792259 likely pathogenic Phenylketonuria 2017-06-13 criteria provided, single submitter clinical testing
Invitae RCV000667759 SCV001235761 pathogenic Phenylketonuria 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 419 of the PAH protein (p.Gln419Arg). This variant is present in population databases (rs752255985, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive phenylalanine hydroxylase deficiency (PMID: 18346471, 28982351). ClinVar contains an entry for this variant (Variation ID: 552488). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 18346471, 21820508). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000667759 SCV004209603 pathogenic Phenylketonuria 2023-08-31 criteria provided, single submitter clinical testing
Natera, Inc. RCV000667759 SCV002088618 pathogenic Phenylketonuria 2020-10-16 no assertion criteria provided clinical testing

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