ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 2019-10-02 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.
Integrated Genetics/Laboratory Corporation of America 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

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