ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.204A>T (p.Arg68Ser) (rs76394784)

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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 RCV000150091 SCV001448287 pathogenic Phenylketonuria 2020-07-24 reviewed by expert panel curation The c.204A>T (p.Arg68Ser) variant in PAH was reported in a Spanish patient with mild/moderate PKU. A defect in the synthesis or regeneration pathways 6R-BH4 was ruled out by analyzing urinary pterin levels and by measuring the dihydropteridine reductase activity (PMID 27121329). It was detected in trans with several pathogenic variants including p.Ala300Ser, p.Asp415Asn, p.Arg158Gln, and c.1315+1G>A (PMID 27121329, 22841515). This variant was found in low frequency in gnomAD (MAF=0.00016) and was predicted deleterious using in silico data. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3 very strong, PM2, PP4 Moderate, and PP3.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078517 SCV000110373 pathogenic not provided 2017-11-13 criteria provided, single submitter clinical testing
Counsyl RCV000150091 SCV000220635 likely pathogenic Phenylketonuria 2014-08-26 criteria provided, single submitter literature only
Invitae RCV000150091 SCV000629187 pathogenic Phenylketonuria 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 68 of the PAH protein (p.Arg68Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs76394784, ExAC 0.007%). This variant has been described as a prevalent Galician variant (PMID: 23500595). It has been reported as compound heterozygous in multiple individuals affected with mild and classic phenylketonuria (PKU) (PMID: 9634518, 11051201, 23500595, 23764561, 23514811). ClinVar contains an entry for this variant (Variation ID: 92738). Experimental studies have shown that this missense change decreases the stability of the PAH protein (PMID: 21953985). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000150091 SCV000696443 pathogenic Phenylketonuria 2016-09-09 criteria provided, single submitter clinical testing Variant summary: The PAH c.204A>T (p.Arg68Ser) variant causes a missense change involving a non-conserved nucleotide with 5/5 in silico tools predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/121282 (1/24271), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. Multiple publications cite the variant in affected compound heterozygote and homozygote individuals. In addition, multiple reputable databases and clinical diagnostic laboratories cite the variant as "likely pathogenic/pathogenic." Therefore, the variant of interest has been classified as a "Pathogenic Variant."
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078517 SCV000888347 pathogenic not provided 2016-08-12 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078517 SCV001250397 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078517 SCV000119467 not provided not provided no assertion provided not provided
Natera, Inc. RCV000150091 SCV001455115 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing

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