Submissions for variant NM_000277.3(PAH):c.739G>C (p.Gly247Arg)

dbSNP: rs62508731

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000668140	SCV000886615	likely pathogenic	Phenylketonuria	2018-12-10	reviewed by expert panel	curation	The c.739G>C (p.Gly247Arg) variant in PAH has been reported in 3 patients with PAH deficiency, with BH4 deficiency assessed in 2 patients. PMID: 21307867, 18985011, 16256386. It was detected with known pathogenic variants R413P (PMID: 16256386) and V388M (PMID: 18985011). It was absent from ExAC, gnomAD, 1000G, and ESP. This variant is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.981. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3.
Counsyl	RCV000668140	SCV000792691	likely pathogenic	Phenylketonuria	2017-07-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000668140	SCV002245610	pathogenic	Phenylketonuria	2023-04-10	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Gly247 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21953985, 26600521). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 102816). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 247 of the PAH protein (p.Gly247Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 16256386, 18985011).
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000668140	SCV005415958	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PM2+PM3_VeryStrong+PP3+PP4
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089071	SCV000119677	not provided	not provided		no assertion provided	not provided