Submissions for variant NM_000277.3(PAH):c.833C>T (p.Thr278Ile)

dbSNP: rs62507262

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000672785	SCV002540152	pathogenic	Phenylketonuria	2022-03-05	reviewed by expert panel	curation	The c.833C>T (p.Thr278Ile) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency ruled out), detected with pathogenic variants: R241C (PMID: 21307867); R241C, A259T (2 patients), R413P, Y356X (PMID: 15503242). Functional studies show a PAH enzyme activity of 1% compared to wild type (PMID: 9860305). This variant is absent in population databases. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4_Moderate, PM2, PP3, PS3_supporting.
Counsyl	RCV000672785	SCV000797926	pathogenic	Phenylketonuria	2018-02-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000672785	SCV000948903	pathogenic	Phenylketonuria	2023-04-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PAH function (PMID: 9860305). 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: 102863). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 9860305, 15503242, 18985011, 23271928). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 278 of the PAH protein (p.Thr278Ile).
Baylor Genetics	RCV000672785	SCV004209692	pathogenic	Phenylketonuria	2023-03-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672785	SCV005203206	pathogenic	Phenylketonuria	2024-07-08	criteria provided, single submitter	clinical testing	Variant summary: PAH c.833C>T (p.Thr278Ile) 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 was absent in 251320 control chromosomes. c.833C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Lee_2004, Lee_2008). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.833C>A, p.Thr278Asn), supporting the critical relevance of codon 278 to PAH protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18985011, 15503242). ClinVar contains an entry for this variant (Variation ID: 102863). Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089124	SCV000119732	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000672785	SCV002088641	pathogenic	Phenylketonuria	2020-11-16	no assertion criteria provided	clinical testing