Submissions for variant NM_000277.3(PAH):c.712A>C (p.Thr238Pro)

gnomAD frequency: 0.00001  dbSNP: rs199475577

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000672442	SCV001443822	likely pathogenic	Phenylketonuria	2020-10-23	reviewed by expert panel	curation	The c.712A>C (p.Thr238Pro) variant in PAH has been reported in 2 individuals with PKU, detected with pathogenic variants p.R408W (PMID: 1363786) and p.R158Q (PMID: 11295882). This variant is absent in population databases. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PP3.
Counsyl	RCV000672442	SCV000797548	uncertain significance	Phenylketonuria	2018-02-06	criteria provided, single submitter	clinical testing
Invitae	RCV000672442	SCV001236278	pathogenic	Phenylketonuria	2022-03-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr238 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 23690520), which suggests that this may be a clinically significant amino acid residue. 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: 102796). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 1363786, 11295882). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 238 of the PAH protein (p.Thr238Pro).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672442	SCV002819525	likely pathogenic	Phenylketonuria	2022-12-14	criteria provided, single submitter	clinical testing	Variant summary: PAH c.712A>C (p.Thr238Pro) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal 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 250808 control chromosomes. c.712A>C has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria), and in at least 3 cases the variant was reported in the compound heterozygous state with a known pathogenic variant (Dworniczak_1992, Rupp_2001, Kuznetcova_2019, Tresbach_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting the same amino acid has been reported in association with Phenylketonuria in HGMD. Two clinical diagnostic laboratories and one expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One submitters classified the variant as pathogenic while one classified as VUS, and the ClinGen PAH Variant Curation Expert Panel has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089047	SCV000119652	not provided	not provided		no assertion provided	not provided