ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.745C>T (p.Leu249Phe) (rs74503222)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000153634 SCV000852151 pathogenic Phenylketonuria 2018-08-12 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. Extremely low frequency in ExAC and gnomAD (0.00004065); PP3: Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.981; PP4_Moderate: L249F was seen 3 times in HPA patients associated with 2 different haplotypes. DHPR defeciency was excluded. Upgraded per ClinGen Metabolic workgroup. (PMID:8533759); PM3_VeryStrong: Seen with R261X, A309V, V388M, R261Q. All Pathogenic/Likely Pathogenic in ClinVar. Upgraded per ClinGen SVI Workgroup (PMID:21871829; PMID:24765287). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3_VeryStrong).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000089076 SCV000203182 pathogenic not provided 2014-04-30 criteria provided, single submitter clinical testing
GeneDx RCV000089076 SCV000239070 pathogenic not provided 2018-09-06 criteria provided, single submitter clinical testing The L249F missense variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. Patients who are homozygous for the L249F variant have been reported with mild phenylketonuria (PKU) (BIOPKU Database).
Invitae RCV000153634 SCV000629213 pathogenic Phenylketonuria 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 249 of the PAH protein (p.Leu249Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs74503222, ExAC 0.004%). This variant has been observed as homozygous or compound heterozygous in multiple individuals affected with PKU or with hyperphenylalaninemia (PMID: 8533759, 24765287, 25155776, 24368688, 1349566, Invitae). ClinVar contains an entry for this variant (Variation ID: 102821). Gene-specific computational analysis of PAH missense mutations has predicted this variant as deleterious (PMID: 25750018). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000153634 SCV000696465 pathogenic Phenylketonuria 2017-05-26 criteria provided, single submitter clinical testing Variant summary: The PAH c.745C>T (p.Leu249Phe) variant located in the Aromatic amino acid hydroxylase, C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome. This variant was found in 3/121308 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). Multiple publications have cited the variant in affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089076 SCV000119682 not provided not provided no assertion provided not provided
Counsyl RCV000153634 SCV000486191 pathogenic Phenylketonuria 2016-05-27 no assertion criteria provided clinical testing

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