ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.165del (p.Phe55fs) (rs199475566)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000642 SCV001146711 pathogenic Phenylketonuria 2019-04-03 reviewed by expert panel curation The c.165delT (p.F55Lfs*6) is a frameshift variant in exon 2 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in compound heterozygote state in multiple patients with PKU (BH4 deficiency not excluded) (PMID: 1682235 & 23500595). The variants in trans include: R408W, and R261Q, both confirmed pathogenic.This variant has an extremely low allele frequency in the Genome Aggregation database (3/251384) (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria: PM2, PP4, PVS1.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078513 SCV000110369 pathogenic not provided 2013-08-27 criteria provided, single submitter clinical testing
GeneDx RCV000078513 SCV000239100 pathogenic not provided 2019-01-18 criteria provided, single submitter clinical testing The c.165delT variant has been reported multiple times in various populations in association with a classic phenylketonuria (PKU) phenotype (Eigel et al. 1991; Alibakhshi et al. 2014; Groselj et al. 2012; Georgiou et al. 2012; Jeannesson-Thivisol et al. 2015; Sterl et al. 2013). It is unclear whether or not the c.165delT variant is responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al. 2008). The c.165delT variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.165delT deletion causes a frameshift starting with codon Phenylalanine 55, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Phe55LeufsX6. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret c.165delT as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078513 SCV000601711 pathogenic not provided 2016-12-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000000642 SCV000696439 pathogenic Phenylketonuria 2016-11-03 criteria provided, single submitter clinical testing Variant summary: The c.165delT (p.Phe55Leufs) variant in PAH gene is a frameshift change that results in the loss of the 393 amino acids of PAH (~85%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. According to the PAH enzymatic activity prediction it is expected to have a residual activity of 0%, which then will lead to elevated level of plasma Phe concentration. These predictions are in line with biochemical data observed in pts homozygous for c.165delT and presented with Classical PKU phenotype (MR, aphasia, elevated Phe plasma level ranging from 1477-2844umol/l). The variant is present in the large control population dataset of ExAC at a low frequency 0.000016 (2/121380 chrs tested). This frequency does not exceed the maximal expected frequency of a pathogenic allele (0.0079) in this gene. The variant has been reported in multiple affected individuals homozygously or in compound heterozygosity via published reports and has been cited as Pathogenic by several reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic.
Invitae RCV000000642 SCV001236492 pathogenic Phenylketonuria 2019-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe55Leufs*6) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs199475566, ExAC 0.003%). This variant has been observed in combination with another PAH variant in individuals affected with phenylketonuria or hyperphenylalaninemia (PMID: 1682235, 18346471, 23500595). ClinVar contains an entry for this variant (Variation ID: 611). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000642 SCV000020792 pathogenic Phenylketonuria 1991-10-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078513 SCV000119439 not provided not provided no assertion provided not provided
Counsyl RCV000000642 SCV000220853 pathogenic Phenylketonuria 2019-07-23 no assertion criteria provided clinical testing

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