ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.969+6T>A

gnomAD frequency: 0.00001  dbSNP: rs62517196
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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 RCV000664529 SCV001250553 uncertain significance Phenylketonuria 2020-01-26 reviewed by expert panel curation The c.969+6T>A variant in PAH has been reported in 2 patients with benign HPA (BH4 deficiency excluded) (PP4_Moderate; PMID: 8659548, 24941924). It was detected with known pathogenic variant c.1162G>A, (p.Val388Met) (PMID: 24941924). This variant has a frequency of 0.00033 in Latino population, which is higher than our PM2 cut-off (0.0002). A deleterious effect is predicted in HSF and TraP. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3, PP3.
Counsyl RCV000664529 SCV000788506 uncertain significance Phenylketonuria 2017-05-12 criteria provided, single submitter clinical testing
Invitae RCV000664529 SCV000828714 pathogenic Phenylketonuria 2024-01-10 criteria provided, single submitter clinical testing This sequence change falls in intron 9 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs62517196, gnomAD 0.03%). This variant has been observed in individual(s) with PAH-related conditions (PMID: 24941924; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102916). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001778708 SCV002015154 uncertain significance not specified 2023-07-05 criteria provided, single submitter clinical testing Variant summary: PAH c.969+6T>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 2/4 computational tools predict a significant impact on weakening of the canonical 5' donor. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.4e-05 in 251198 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (4.4e-05 vs 0.0079), allowing no conclusion about variant significance. c.969+6T>A has been reported in the literature in settings of newborn screening in newborns with MHP (mild hyperphenylalaninemia), in compound heterozygosity with a pathogenic PAH allele (c.1162G>A, p.Val388Met) in a newborn with Benign HPA, and as a non-informative genotype in the NBSeq project cohort that evaluated whole-exome sequencing (WES) as an innovative methodology for NBS (example, Guldberg_1996, Yang_2001, Vela-Amieva_2015, Hillert_2020, Adhikari_2020, Vela-Amieva_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32778825, 8659548, 32668217, 24941924, 34828281, 11385716). Four submitters (including ClinGen PAH Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity Omics RCV000664529 SCV003816611 uncertain significance Phenylketonuria 2022-08-03 criteria provided, single submitter clinical testing
Baylor Genetics RCV000664529 SCV004209566 pathogenic Phenylketonuria 2023-10-02 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089182 SCV000119797 not provided not provided no assertion provided not provided

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