Submissions for variant NM_000277.3(PAH):c.520A>G (p.Ile174Val)

gnomAD frequency: 0.00001  dbSNP: rs199475632

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000675155	SCV000852115	likely pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: Not found in any population databases; PP3: All predictors agree--damaging; PM3: Single patient IVS4+5G>T (null) / I174V (Bercovich 2008 PMID 18299955) (PMID:18299955); PP4: Two independent patients (one in Zschocke (PMID 10394930) and one in Bercovich (PMID 18299955) with "PKU". While no specific levels are mentioned, they are followed in clinic and were diagnosed with Phe >120umol/L. BH4 defect WAS NOT excluded in either paper.. In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PM3, PP4).
Eurofins Ntd Llc (ga)	RCV000088968	SCV000203187	uncertain significance	not provided	2015-09-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000675155	SCV001220737	pathogenic	Phenylketonuria	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 174 of the PAH protein (p.Ile174Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 18299955, 22526846, 27121329). ClinVar contains an entry for this variant (Variation ID: 102720). 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%. This variant disrupts the p.Ile174 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 23842451), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000675155	SCV001361067	pathogenic	Phenylketonuria	2019-08-05	criteria provided, single submitter	clinical testing	Variant summary: PAH c.520A>G (p.Ile174Val) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251110 control chromosomes. c.520A>G has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (mild-PKU/Non-PKU-HPA, Phenylketonuria)(Zschocke_1999, Bercovich_2008, Couce_2013, Yang_2001, Sterl_2013, Reblova_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories (n=1, Likely pathogenic; n=1, VOUS) and one expert panel (Likely pathogenic, ClinGen) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000088968	SCV001370959	pathogenic	not provided	2020-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000088968	SCV001873768	pathogenic	not provided	2023-07-13	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17924342, 30311390, 23500595, 27121329, 10394930, 27308838, 29997390, 23357515, 22526846, 18299955, 18294361, 11385716, 32668217)
Baylor Genetics	RCV000675155	SCV004209617	likely pathogenic	Phenylketonuria	2023-08-16	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088968	SCV000119571	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000675155	SCV000800768	likely pathogenic	Phenylketonuria	2017-06-02	no assertion criteria provided	clinical testing