ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.529G>C (p.Val177Leu) (rs199475602)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000669836 SCV001762307 pathogenic Phenylketonuria 2019-09-22 reviewed by expert panel curation The c.529G>C (p.Val177Leu) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate). This variant has an extremely low allele frequency (Pop Max MAF=0.00005 ENF) in gnomAD (PM2). This variant was detected with pathogenic variants: F39L, L48S, F39del, R408W, R261Q, F55fs, R158Q, Trp187*. Parental testing not reported. PMID: 8659548, PMID: 16879198, PMID: 19609714, PMID: 23430918, PMID: 22391997, PMID: 22513348, PMID: 26666653 (PM3_very-strong. Computational prediction tools and conservation analysis do not agree. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_very-strong, PM2.
GeneDx RCV000088976 SCV000490679 pathogenic not provided 2018-05-31 criteria provided, single submitter clinical testing The V177L variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The V177L variant has previously been reported in association with mild phenylketonuria (PKU) and hyperphenylalaninemia (Eiken et al., 1996; Réblová et al.,2013; Jeannesson-Thivisol et al., 2015). Tetrahydrobiopterin (BH4) responsiveness is inconsistent in patients with V177L (Zurfluh et al., 2008; Sarkissian et al., 2012; Anjema et al., 2013). Therefore, we interpret V177L in PAH as a pathogenic variant.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000669836 SCV000891287 likely pathogenic Phenylketonuria 2017-10-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000669836 SCV000917922 pathogenic Phenylketonuria 2018-05-14 criteria provided, single submitter clinical testing Variant summary: PAH c.529G>C (p.Val177Leu) results in a conservative amino acid change located in the catalytic domain of the encoded protein sequence (Jeannesson-Thivisol 2015). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 276898 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (2.9e-05 vs 0.0079), allowing no conclusion about variant significance. The variant, c.529G>C has been reported in the literature in multiple individuals affected with mild Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and also found in individuals with Hyperphenylalaninemia (e.g. Djordjevic 2012, Sterl 2013, Reblova 2013, Anjema 2013, Jeannesson-Thivisol2015). These data indicate that the variant is very likely to be associated with disease. Tetrahydrobiopterin (BH4) responsiveness was reported to be inconsistent in patients, probably influenced by the other variant found in trans (Djordjevic 2012, Anjema 2013). In a recent study a compound heterozygous patient carrying this mutation with a null mutation, was found to be BH4-responsive (Jeannesson-Thivisol 2015). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000669836 SCV001232783 pathogenic Phenylketonuria 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 177 of the PAH protein (p.Val177Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs199475602, ExAC 0.008%). This variant has been observed in combination with another PAH variants in several individuals affected with PAH-related conditions (PMID: 8659548, 8807331, 23430547, 22513348, 26666653, 24789341, 25087612). ClinVar contains an entry for this variant (Variation ID: 102727). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Not Available; PolyPhen-2: Benign; Align-GVGD: Not Available). This variant disrupts the p.Val177 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23500595, 12501224, 27121329, 23430547, 23764561, 17096675). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000088976 SCV001250395 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088976 SCV000119579 not provided not provided no assertion provided not provided
Counsyl RCV000669836 SCV000794628 pathogenic Phenylketonuria 2017-10-02 no assertion criteria provided clinical testing

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