Submissions for variant NM_000277.3(PAH):c.283A>T (p.Ile95Phe)

gnomAD frequency: 0.00002  dbSNP: rs62508682

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000763292	SCV005442787	likely pathogenic	Phenylketonuria	2024-09-06	reviewed by expert panel	curation	The c.283A>T (p.Ile95Phe) variant in PAH has been reported in multiple patients with mild and moderate phenylketonuria. It was detected with pathogenic variants: p.R408W (PMID: 10495930); p.R158Q, p.A403V, p.T323del (PMID: 18299955); and p.E280K (PMID: 31623983). This variant has a MAF of 0.00060 in gnomAD in the Ashkenazi Jewish population, which is above our cutoff for PM2 (<0.0002) and below our cutoff for BS1 (>0.002). Computational evidence support a deleterious effect (REVEL=0.658). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP3, PP4.
GeneDx	RCV000088890	SCV000329447	likely pathogenic	not provided	2024-05-14	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10495930, 29144512, 18299955, 11096279, 32668217, 18294361, 11678552, 31623983)
Fulgent Genetics, Fulgent Genetics	RCV000763292	SCV000893953	likely pathogenic	Phenylketonuria	2021-09-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000763292	SCV000919908	pathogenic	Phenylketonuria	2020-11-02	criteria provided, single submitter	clinical testing	Variant summary: PAH c.283A>T (p.Ile95Phe) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251440 control chromosomes (gnomAD). c.283A>T has been reported in the literature in individuals (compound heterozygous) affected with mild and moderate Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Bercovich_2008, Zekanowski_1999, Rajabi_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000763292	SCV001380546	pathogenic	Phenylketonuria	2024-03-24	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 95 of the PAH protein (p.Ile95Phe). This variant is present in population databases (rs62508682, gnomAD 0.05%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 10495930, 18299955, 32668217; BIOPKU http://www.biopku.org). ClinVar contains an entry for this variant (Variation ID: 102645). 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.
Baylor Genetics	RCV000763292	SCV004201380	pathogenic	Phenylketonuria	2024-03-02	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088890	SCV000119487	not provided	not provided		no assertion provided	not provided