Submissions for variant NM_000277.3(PAH):c.620A>G (p.Asn207Ser)

dbSNP: rs62508721

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000668775	SCV004015309	likely pathogenic	Phenylketonuria	2023-07-23	reviewed by expert panel	curation	The NM_000277.3:c.620A>G variant in PAH is a missense variant predicted to cause substitution of asparagine by serine at amino acid 207 (p.Asn207Ser). This variant has been detected in at least 5 unrelated individuals with PAH deficiency (PMID: 32668217, PMID: 9048935). Of these individuals, one was a compound heterozygote for the variant and a likely pathogenic variant, p.Pro281Leu, in trans (phase confirmed by parental testing) (PMID: 9048935), and four were compound heterozygotes for the variant and pathogenic variants, p.Ala300Ser, p.Ala403Val, p.Glu390Gly, p.Arg252Gln, in unknown phase (PMID: 32668217) (3pts total, PM3_Strong). One of these individuals had plasma phenylalanine >120 μmol/L without the exclusion of a defect of BH4 cofactor metabolism (PMID: 9048935) (PP4). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.77 which is above the threshold of 0.75, evidence that correlates with impact to PAH function (PP3). There is a ClinVar entry for this variant (Variation ID: 102765, 1 star review status) with one submitter classifying the variant as pathogenic, one submitter classifying the variant as likely pathogenic, and one submitter classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as likely pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, PM3_Strong, PP3, PP4.
Counsyl	RCV000668775	SCV000793428	uncertain significance	Phenylketonuria	2017-08-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000668775	SCV001213212	pathogenic	Phenylketonuria	2022-03-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn207 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9452061, 12554741). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 102765). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 9048935, 17096675, 31332730). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 207 of the PAH protein (p.Asn207Ser).
Genome-Nilou Lab	RCV000668775	SCV001810506	likely pathogenic	Phenylketonuria	2021-07-22	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089015	SCV000119619	not provided	not provided		no assertion provided	not provided