Submissions for variant NM_000277.3(PAH):c.569T>C (p.Val190Ala)

gnomAD frequency: 0.00001  dbSNP: rs62514919

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000632878	SCV000754078	pathogenic	Phenylketonuria	2023-09-08	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 190 of the PAH protein (p.Val190Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PAH-related diseases (PMID: 9452062, 11486900, 17502162, 26666653; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102740). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PAH protein function. Experimental studies have shown that this missense change does not substantially affect PAH function (PMID: 15557004). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000632878	SCV000788960	pathogenic	Phenylketonuria	2017-01-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000632878	SCV001370579	pathogenic	Phenylketonuria	2020-05-25	criteria provided, single submitter	clinical testing	Variant summary: PAH c.569T>C (p.Val190Ala) 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 251330 control chromosomes. c.569T>C has been reported in the literature among compound heterozygote genotypes in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Michiels_1998, Spaapen_2001, Dobrowlski_2007, Jeannesson-Thivisol_2015, Kuznetcova_2019, Quirk_2012). These data indicate that the variant is very likely to be associated with disease. Several publications report conflicting experimental evidence evaluating an impact on protein function (example, Erlandsen_2004, Zurfluh_2008, Himmelreich_2018). The most pronounced variant effect results in 30%-50% of normal activity (Himmelreich_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000632878	SCV004201350	pathogenic	Phenylketonuria	2023-10-22	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088989	SCV000119593	not provided	not provided		no assertion provided	not provided