ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.281TCA[1] (p.Ile95del) (rs62508727)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000635 SCV001250569 pathogenic Phenylketonuria 2019-10-18 reviewed by expert panel curation This variant was documented in 8 patients diagnosed with PAH deficiency (PMID: 26503515, 30747360, 30050108, 29560316, 18985011). Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay. This variant was detected in trans with a pathogenic or likely pathogenic PAH variant in 2 patients with PKU and 3 patients with hyperphenylalaninemia (PMID: 19292873, 24368688, 25894915, 26666653, 29316886). This variant is present at a frequency below 0.0002 in the population databases ExAC and gnomAD. This variant changes protein length from an in-frame deletion in a non-repeat region. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM4, PP4_moderate.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078518 SCV000110374 pathogenic not provided 2013-02-06 criteria provided, single submitter clinical testing
GeneDx RCV000078518 SCV000239098 pathogenic not provided 2017-03-31 criteria provided, single submitter clinical testing The c.284_286delTCA pathogenic variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The c.284_286delTCA variant causesthe loss of a single Isoleucine codon at position 95 of the phenylalanine hydroxylase protein, denotedp.Ile95del. In vitro enzyme studies found that this variant is associated with 27% residualphenylalanine hydroxylase activity (Song et al., 2005). This variant was reported homozygous in amother and her child; both had a mild PKU presentation (Caillaud et al., 1991). Responsiveness toBH4 therapy in patients harboring the c.284_286delTCA variant has been inconsistent (Zurfluh et al.,2008; Jeannesson-Thivisol et al., 2015).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078518 SCV000601712 pathogenic not provided 2017-04-07 criteria provided, single submitter clinical testing
Invitae RCV000000635 SCV000629189 pathogenic Phenylketonuria 2020-01-31 criteria provided, single submitter clinical testing This variant, c.284_286delTCA, results in the deletion of 1 amino acid of the PAH protein (p.Ile95del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs62508727, ExAC 0.01%). This variant has been reported as homozygous or in combination with another PAH variant in several individuals affected with phenylketonuria and hyperphenylalaninemia, and was found to segregate with the disease in one family (PMID: 14722928, 1709636, 17096675, 18985011, 19292873, 23430918, 25894915, 26666653). This variant is also known as p.Ile94del in the literature. ClinVar contains an entry for this variant (Variation ID: 604). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. For these reasons, this variant has been classified as Pathogenic.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000000635 SCV001251471 pathogenic Phenylketonuria criteria provided, single submitter research The PAH c.284_286delTCA (p.I95del) variant results in a deletion of a single amino acid and has been observed in homozygous and compound heterozygous state in individuals with phenylketonuria. This variant has previously been shown to result in a reduced affinity of the PAH enzyme for phenylalanine (PMID: 1709636; 18985011; 19292873; 25894915; 26666653).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000000635 SCV001372242 pathogenic Phenylketonuria 2020-06-15 criteria provided, single submitter clinical testing Variant summary: PAH c.284_286delTCA (p.Ile95del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 251448 control chromosomes. c.284_286delTCA has been well reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Chien_2004, Daniele_2007, Caillaud_1991). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity (Maximal velocity/Km) due to a markedly decreased subtrate specificity (increased Km) for Phenylalanine (Caillaud_1991). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=4)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000000635 SCV000020785 pathogenic Phenylketonuria 2007-08-15 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078518 SCV000119488 not provided not provided no assertion provided not provided
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078518 SCV000119489 not provided not provided no assertion provided not provided
Counsyl RCV000000635 SCV000485292 likely pathogenic Phenylketonuria 2016-05-19 no assertion criteria provided clinical testing
Natera, Inc. RCV000000635 SCV001455112 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing

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