Submissions for variant NM_000277.3(PAH):c.241A>C (p.Thr81Pro)

gnomAD frequency: 0.00001  dbSNP: rs62509017

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001192889	SCV005442782	likely pathogenic	Phenylketonuria	2024-11-17	reviewed by expert panel	curation	The c.241A>C (p.Thr81Pro) variant in PAH has been reported in at least two individuals with classic PKU, where it was observed without confirmed phase with c.117C>G (p.Phe39Leu) (classified as pathogenic by PAH VCEP Variation ID 605) and c.842+1G>A (classified as pathogenic by PAH VCEP Variation ID 599) (PMID: 8659548, PMID: 9169088, PMID: 11328945). It has also been described without a specified subtype or phase with two additional pathogenic variants: p.R408W (Variation ID: 577, PMID: 23430918); c.822_832del (p.Lys274fs) (Variation ID: 102852, PMID: 23430918). Exclusion of BH4 deficiency was not specified. In-vitro functional studies are unavailable. This variant has extremely low frequency in gnomAD v4.1.0 (MAF=0.000007629). In-silico predictions support pathogenicity of this variant (REVEL=0.74). Another missense variant [c.242C>A (p.Thr81Asn)] in the same codon has been classified as likely pathogenic by the ClinGen Phenylketonuria Variant Curation Expert Panel. In summary, this variant is likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4, PM2_supporting, PM5_supporting, PP3.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000088881	SCV001134523	pathogenic	not provided	2023-11-17	criteria provided, single submitter	clinical testing	The PAH c.241A>C (p.Thr81Pro) variant has been reported in the published literature in individuals with Phenylketonuria (PKU), including classical PKU cases and maternal PKU cases (PMIDs: 32668217 (2020), 23430918 (2012), 11328945 (2001), 10541324 (1999), 10429004 (1999), 9169088 (1997), 8659548 (1996)). Additionally, this variant has been associated with BH4 unresponsiveness (PMID: 23430918 (2012)). The frequency of this variant in the general population, 0.000015 (1/68014 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192889	SCV001361329	likely pathogenic	Phenylketonuria	2019-10-31	criteria provided, single submitter	clinical testing	Variant summary: PAH c.241A>C (p.Thr81Pro) results in a non-conservative amino acid change located in the ACT domain (IPR002912) 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 251436 control chromosomes (gnomAD). c.241A>C has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Guldberg_1996, Sarkissian_2012, Enns_1999). These data indicate that the variant is likely to be associated with disease. Another variant affecting the same codon (c.242C>A, p.T81N) has been classified as likely pathogenic in ClinVar by the ClinGen PAH Variant Curation Expert Panel (Variation ID: 208180). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001192889	SCV001414753	pathogenic	Phenylketonuria	2023-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 81 of the PAH protein (p.Thr81Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 8659548, 23430918). ClinVar contains an entry for this variant (Variation ID: 102637). 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	RCV001192889	SCV004209676	pathogenic	Phenylketonuria	2023-04-25	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088881	SCV000119478	not provided	not provided		no assertion provided	not provided