ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.434A>T (p.Asp145Val) (rs140175796)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel, RCV000546355 SCV000886564 likely pathogenic Phenylketonuria 2018-12-10 reviewed by expert panel curation The c.434A>T (p.Asp145Val) PAH variant has been identified in patients with PAH deficiency from the US, Germany, Italy and Spain. BH4 deficiency was excluded. (PMID: 8659548; 11385716; 12655553; 17096675; 23514811) It was detected with known pathogenic variants: V388M (PMID: 8659548), I65T (PMID: 24368688), and R408W (PMID: 26666653). It is found at extremely low frequency (MAF 0.00012 in gnomAD). A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.987. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088915 SCV000119513 not provided not provided no assertion provided not provided
GeneDx RCV000088915 SCV000490677 pathogenic not provided 2016-10-26 criteria provided, single submitter clinical testing the D145V variant has been reported as a pathogenic variant in the PAH Consortium database. The D145V missense variant has been reported in association with mild phenylketonuria (PKU) and mild hyperphenylalaninemia (HPA) (Guldberg et al. 1996; Güttler et al. 1999; Acosta et al. 2001; Ho et al. 2014; Jeannesson-Thivisol et al. 2015; Ohlsson et al. 2016). D145V is located in the catalytic domain of the phenylalanine hydroxylase enzyme (Jeannesson-Thivisol et al. 2015). This variant has been reported to be responsive to tetrahydrobiopterin (BH4) therapy (Ho et al. 2014; Jeannesson-Thivisol et al. 2015). We interpret D145V to be a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000546355 SCV000914556 pathogenic Phenylketonuria 2018-12-11 criteria provided, single submitter clinical testing The PAH c.434A>T (p.Asp145Val) missense variant has been reported in seven studies in which it is found in a total of seven individuals in a compound heterozygous state, and in one in a heterozygous state with no second variant detected (Guldberg et al. 1996, Mallolas et al. 1999, Yang et al. 2001, Aulehla-Scholz et al. 2003, Dahri et al. 2010, Ho et al. 2013, Jeannesson-Thivisol et al. 2015). Individuals with the p.Asp145Val variant were described as having mild hyperphenylalaninemia. The p.Asp145Val variant was absent from 620 healthy controls (Aulehla-Scholz et al. 2003, Ho et al. 2014) and is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Asp145Val variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000546355 SCV000696447 pathogenic Phenylketonuria 2017-08-25 criteria provided, single submitter clinical testing Variant summary: The PAH c.434A>T (p.Asp145Val) variant involves the alteration of a highly conserved nucleotide located in the catalytic domain of the protein. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 5/121412 control chromosomes at a frequency of 0.0000412, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been identified in several affected individuals with biochemically confirmed mild form of HPA or PKU, and was predicted to be BH4-responsive allele. In addition,at least one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000546355 SCV000629192 pathogenic Phenylketonuria 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 145 of the PAH protein (p.Asp145Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs140175796, ExAC 0.01%). This variant has been reported in combination with another PAH variant in individuals affected with hyperphenylalaninemia and pheynylketonuria (PMID: 8659548, 27469133, 26666653, 24368688). ClinVar contains an entry for this variant (Variation ID: 102667). This variant has been observed in individuals with phenylalanine levels >180 umol/L findings that are highly specific for hyperphenylalaninemia (PMID: 8659548, 26666653). Experimental studies have shown that this missense change impairs PAH enzyme function (PMID: 27121329). For these reasons, this variant has been classified as Pathogenic.

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