Submissions for variant NM_000277.3(PAH):c.508C>G (p.His170Asp)

gnomAD frequency: 0.00002  dbSNP: rs199475655

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000150088	SCV000852149	pathogenic	Phenylketonuria	2018-07-28	reviewed by expert panel	curation	The c.508C>G (p.His170Asp) variant in PAH has been reported in 1 patient with hyperphenylalaninemia, and 1 patient with benign persistent hyperphenylalaninemia. (PP4; PMID: 11385716). This variant has an extremely low allele frequency (0.00018) in gnomAD (PM2; http://gnomad.broadinstitute.org). This variant has 43% enzyme activity (PS3; PMID: 17935162). This variant was detected in trans with R261X, c.60+5G>T, c.1315+1G>A (Pathogenic in ClinVar) (PM3_Strong; PMID: 11385716; PMID: 24941924). Computational prediction tools and conservation analysis suggest that the c.829T>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3, PM3_Strong
Eurofins Ntd Llc (ga)	RCV000078524	SCV000110380	pathogenic	not provided	2013-08-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000078524	SCV000239056	pathogenic	not provided	2018-09-24	criteria provided, single submitter	clinical testing	The H170D missense variants in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The H170D has been reported previously in association with both mild phenylketonuria (PKU) and with hyperphenylalaninemia (Yang et al., 2001; Vela-Amieva et al., 2015). Functional analysis found that H170D is associated with significant residual enzyme activity and is classified as a BH4-responsive variant (Zurfluh et al. 2008).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000150088	SCV000629195	pathogenic	Phenylketonuria	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 170 of the PAH protein (p.His170Asp). This variant is present in population databases (rs199475655, gnomAD 0.01%). This missense change has been observed in individual(s) with benign persistent hyperphenylalaninemia and hyperphenylalaninemia (PMID: 11385716, 12971421). ClinVar contains an entry for this variant (Variation ID: 92744). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PAH function (PMID: 15557004, 17935162). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000150088	SCV004201346	pathogenic	Phenylketonuria	2024-01-16	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078524	SCV000119557	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000150088	SCV001455099	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing