Submissions for variant NM_000277.3(PAH):c.301G>A (p.Asp101Asn)

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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	RCV000669377	SCV001370875	likely pathogenic	Phenylketonuria	2020-04-10	reviewed by expert panel	curation	The c.301G>A (p.Asp101Asn) variant in PAH has been reported in 3 patients with PKU (BH4 deficiency excluded) (PMID: 26503515, 26600521, 28982351). This variant is absent from controls in ExAC, gnomAD, 1000 Genomes, ESP. Conflicting computational evidence: SIFT (T); PolyPhen-2 (B); MutationTaster (D); REVEL=0.465. It is detected in trans with pathogenic variants Q267E and p.Arg158Trp. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong.
Counsyl	RCV000669377	SCV000794125	uncertain significance	Phenylketonuria	2017-09-14	criteria provided, single submitter	clinical testing
Invitae	RCV000669377	SCV000936489	pathogenic	Phenylketonuria	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 101 of the PAH protein (p.Asp101Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 28982351). ClinVar contains an entry for this variant (Variation ID: 553851). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000669377	SCV001339025	pathogenic	Phenylketonuria	2020-03-09	criteria provided, single submitter	clinical testing	Variant summary: PAH c.301G>A (p.Asp101Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251456 control chromosomes. c.301G>A has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and HPA (Li_2015, Liu_2017, Wang_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000669377	SCV004209624	pathogenic	Phenylketonuria	2023-08-05	criteria provided, single submitter	clinical testing

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