Submissions for variant NM_000277.3(PAH):c.1074A>T (p.Leu358Phe)

dbSNP: rs376480977

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000672872	SCV001762335	likely pathogenic	Phenylketonuria	2021-07-25	reviewed by expert panel	curation	The c.1074A>T (p.Leu358Phe) variant in PAH meets criteria to be classified as likely pathogenic. PAH-specific ACMG/AMP criteria applied: PM2: Variant is present at low frequency in gnomAD (0.0000) and ExAC (0.00002). Absent from 1000 Genomes. PM3: Found to co-occur with F331S in one patient with mild HPA, but no additional studies to demonstrate phase of variants (PMID: 23764561). Found to co-occur with other non-PKU HPA mutation I306V, phase was not confirmed (PMID: 23357515). Found to co-occur in two patients with L348V and R408W with mild and classic PKU, respectively. (PMID: 24350308) PP3: Predicted to be damaging (SIFT), probably damaging (PolyPhen2), Disease causing (MutationTaster). PP4: In both studies, patients were recruited for their abnormal Phelevels defined as HPA <600umol or 120-600umol. There was no additional testing done to rule out other similar analyte disorders. PS3_Not Met: Functional studies in E. Coli model used and relative specific activity of L358F is 52+-0.7%, which is above our 50% threshold to apply this line of evidence.
Counsyl	RCV000672872	SCV000798020	uncertain significance	Phenylketonuria	2018-02-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000672872	SCV000940771	pathogenic	Phenylketonuria	2024-03-21	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 358 of the PAH protein (p.Leu358Phe). This variant is present in population databases (rs376480977, gnomAD 0.002%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 23357515, 23764561, 24350308; Invitae). ClinVar contains an entry for this variant (Variation ID: 556817). 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: 28653649). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000672872	SCV002797772	pathogenic	Phenylketonuria	2022-04-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000672872	SCV004209604	pathogenic	Phenylketonuria	2024-02-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672872	SCV005039168	likely pathogenic	Phenylketonuria	2024-03-25	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1074A>T (p.Leu358Phe) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251142 control chromosomes (gnomAD). c.1074A>T has been reported in the literature in individuals affected with hyperphenylalaninemia (examples: Reblova_2013, Polak_2013, Bik-Multanowski_2022). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35176108, 28653649, 23764561, 23357515). ClinVar contains an entry for this variant (Variation ID: 556817). Based on the evidence outlined above, the variant was classified as likely pathogenic.