ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.508C>G (p.His170Asp) (rs199475655)

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Total submissions: 5
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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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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).
Invitae RCV000150088 SCV000629195 pathogenic Phenylketonuria 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 170 of the PAH protein (p.His170Asp). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported as compound heterozygous in individuals affected with hyperphenylalaninemia (PMID: 11385716, 12971421) or as homozygous in an individual with benign persistent hyperphenylalaninemia (PMID: 11385716). ClinVar contains an entry for this variant (Variation ID: 92744). Experimental studies have shown that this variant affects PAH protein function although there is a significant retention of enzyme activity (PMID: 17935162, 15557004). In summary, this variant is a rare missense change that has been observed in patients affected with PAH-related conditions and shown to reduce the activity of the encoded enzyme. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078524 SCV000119557 not provided not provided no assertion provided not provided

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