ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.740G>T (p.Gly247Val) (rs199475579)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169396 SCV000220792 likely pathogenic Phenylketonuria 2014-10-14 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000089073 SCV000857831 pathogenic not provided 2017-11-13 criteria provided, single submitter clinical testing
Invitae RCV000169396 SCV000946467 pathogenic Phenylketonuria 2019-01-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 247 of the PAH protein (p.Gly247Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with phenylketonuria (PMID: 26600521). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102818). This variant has been reported to affect PAH protein function (PMID: 21953985, 17924342). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000169396 SCV001337905 pathogenic Phenylketonuria 2020-01-10 criteria provided, single submitter clinical testing Variant summary: PAH c.740G>T (p.Gly247Val) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251220 control chromosomes. c.740G>T has been frequently reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Li_2018). 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 activity reporting a functionally hemizygous genotype in combination with null mutations (Li_2018). Two 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. Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089073 SCV000119679 not provided not provided no assertion provided not provided

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