ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.*19G>T (rs372637021)

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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 RCV000538868 SCV001146700 uncertain significance Phenylketonuria 2019-09-27 reviewed by expert panel curation The c.*19G>T variant in PAH has been reported in a 2 patients with PKU (PP4; PMID: 12765842, 26210745) This variant has an allele frequency greater than expected: gnomAD MAF=0.00812 (>0.002) and 8 homozygotes (BS1). Computational evidence is conflicting (TraP score: 0.085; HSF: activation of an exonic cryptic donor site; MaxENT 3' Motif:+1145.71). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, BS1.
PreventionGenetics,PreventionGenetics RCV000252084 SCV000303440 likely benign not specified criteria provided, single submitter clinical testing
GeneDx RCV000252084 SCV000521187 likely benign not specified 2017-08-17 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000252084 SCV000601704 likely benign not specified 2017-07-17 criteria provided, single submitter clinical testing
Invitae RCV000538868 SCV000629166 benign Phenylketonuria 2019-12-31 criteria provided, single submitter clinical testing
Counsyl RCV000538868 SCV000788498 uncertain significance Phenylketonuria 2017-04-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000252084 SCV000917925 likely benign not specified 2018-05-24 criteria provided, single submitter clinical testing Variant summary: PAH c.*19G>T is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.002 in 276672 control chromosomes, predominantly at a frequency of 0.0081 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. This frequency is higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.0081 vs 0.0079), suggesting this variant is likely a benign polymorphism especially for South Asians. The variant, c.*19G>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (da Silva_2003, Trunzo_2015). Co-occurrences with other pathogenic variant(s) have been reported (PAH c.1223G>A, p.R408Q), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as likely benign.

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