ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.963C>T (p.Leu321=) (rs61747292)

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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 RCV000721181 SCV000852147 benign Phenylketonuria 2018-07-29 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: BS1: >0.02% as set by the PAH specific specifications; BP7: ; BS3_Supporting: cDNA method demonstrates 98% and intinic system demonstrates 81% residual enzyme activity; BS2: 38 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, BP7, BS3_Supporting, BS2).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507684 SCV000601720 benign not specified 2016-10-12 criteria provided, single submitter clinical testing
GeneDx RCV000507684 SCV000729359 benign not specified 2018-02-27 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 RCV000721181 SCV001012192 benign Phenylketonuria 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000721181 SCV001271162 likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Integrated Genetics/Laboratory Corporation of America RCV000507684 SCV001361062 benign not specified 2019-06-17 criteria provided, single submitter clinical testing Variant summary: PAH c.963C>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 0.0039 in 251262 control chromosomes, predominantly at a frequency of 0.053 within the African or African-American subpopulation in the gnomAD database, including 26 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 7-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) phenotype (0.0079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Three ClinVar submissions from clinical diagnostic laboratories and an expert panel (ClinGen)(evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089175 SCV000119790 not provided not provided no assertion provided not provided

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