ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.472C>T (p.Arg158Trp) (rs75166491)

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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 RCV000409986 SCV000852152 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ExAC MAF=0.00019.; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.939; PS3: 2% mutant enzyme activity in BioPKU; PP4_Moderate: Detected in at least 3 patients with PAH deficiency. BH4 deficiency ruled out in 1 patient. (PMID:1307609; PMID:10429004; PMID:9634518); PM3_Strong: Detected with 3 pathogenic/likely pathogenic variants (PMID:14681498; PMID:23430918). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PP4_Moderate, PM3_Strong).
GeneDx RCV000088941 SCV000581901 pathogenic not provided 2018-02-01 criteria provided, single submitter clinical testing The R158W missense variant in the PAH gene has been reported as a pathogenic variant in thePAH Consortium database. The R158W variant has been reported in a homozygous state in an individual withmild-moderate PKU (Jeannesson-Thivisol et al., 2015); however, this variant has also been identified in individualswith classic PKU (Yamashita et al., 1992; Bashyam et al., 2014; Jeannesson-Thivisol et al., 2015; Danecka et al.,2015). Therefore, genotype/phenotype predictions for the R158W variant cannot be made at this time. Functionalanalysis found that R158W is associated with 1.8% residual enzyme activity compared to wild type (Danecka et al.,2015). It is unclear if R158W is responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al., 2008; Jeannesson-Thivisol et al., 2015). The R158 site is important for maintaining PAH active site structure as it is involved in saltbridge formation (Baysham et al., 2014). A missense variant at the same residue (R158Q) has been reported in theHuman Gene Mutation Database in association with PKU (Stenson et al., 2014), further supporting the functionalimportance of this region of the protein. In summary, we interpret R158W as pathogenic.
Invitae RCV000409986 SCV000818627 pathogenic Phenylketonuria 2018-03-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 158 of the PAH protein (p.Arg158Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs75166491, ExAC 0.02%). This variant has been reported as homozygous or in combination with another PAH variant in multiple individuals affected with phenylketonuria (PKU) (PMID: 10356314, 14681498, 20082265, 25894915, 26666653, 24130151, 20082265, 24941924, 19609714, 23430918). ClinVar contains an entry for this variant (Variation ID: 102693). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Arg158Gln) has been determined to be pathogenic (PMID: 2014036, 25596310, 23500595, 10479481, 24368688). This suggests that the arginine residue is critical for PAH protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088941 SCV000119541 not provided not provided no assertion provided not provided
Counsyl RCV000409986 SCV000485294 pathogenic Phenylketonuria 2016-01-21 no assertion criteria provided clinical testing

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