ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1242C>T (p.Tyr414=) (rs1801152)

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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 RCV000541061 SCV000852150 benign Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: BS1: MAF=0.01361 in ENF from gnomAD; BS2: 19 homozygotes in gnomAD. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, BS2).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000174235 SCV000225502 benign not specified 2015-02-18 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000174235 SCV000303441 benign not specified criteria provided, single submitter clinical testing
GeneDx RCV000174235 SCV000515909 likely benign not specified 2016-02-15 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000541061 SCV000629183 benign Phenylketonuria 2019-12-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000088814 SCV000889564 benign not provided 2018-04-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000174235 SCV000917926 benign not specified 2018-05-29 criteria provided, single submitter clinical testing Variant summary: PAH c.1242C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0074 in 277168 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.014 (in the gnomAD database), including 16 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.77 fold of the estimated maximal expected allele frequency for a pathogenic variant in PAH causing Hyperphenylalaninemia phenotype (0.0079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no experimental evidence demonstrating its impact on protein function has been reported. Three 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 benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV000541061 SCV001268942 benign Phenylketonuria 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088814 SCV000119405 not provided not provided no assertion provided not provided

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