Submissions for variant NM_000277.3(PAH):c.275C>T (p.Thr92Ile)

gnomAD frequency: 0.00001  dbSNP: rs62514903

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854512	SCV002238710	pathogenic	Phenylketonuria	2025-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 92 of the PAH protein (p.Thr92Ile). This variant is present in population databases (rs62514903, gnomAD 0.0009%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 11708866, 16198137, 16601866). ClinVar contains an entry for this variant (Variation ID: 102643). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PAH function (PMID: 11708866). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001854512	SCV004209674	pathogenic	Phenylketonuria	2024-03-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000088888	SCV005326121	likely pathogenic	not provided	2023-09-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21953985, 11708866, 8268925, 25087612, 9781015, 16198137, 17935162, 16601866, 32668217)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001854512	SCV005884041	pathogenic	Phenylketonuria	2024-12-27	criteria provided, single submitter	clinical testing	Variant summary: PAH c.275C>T (p.Thr92Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251432 control chromosomes. c.275C>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 76% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 9399896, 31332730, 17935162). ClinVar contains an entry for this variant (Variation ID: 102643). Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088888	SCV000119485	not provided	not provided		no assertion provided	not provided