Total submissions: 14
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000150089 | SCV000852117 | pathogenic | Phenylketonuria | 2018-05-24 | reviewed by expert panel | curation | The c.441+5G>T variant in PAH has been reported on >17 PKU alleles (BH4 deficiency excluded). (PP4_Moderate; PMID: 17935162; PMID: 23514811). This variant has an extremely low allele frequency (0.00002886) in gnomAD (PM2; http://gnomad.broadinstitute.org). This variant has 0% enzyme activity (PS3; http://www.biopku.org). This variant was detected in trans with IVS10-11g>a and p.V388M (Pathogenic in ClinVar) (PM3_Strong; PMID: 23514811). Computational prediction tools and conservation analysis suggest that the c.441+5G>T variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Strong |
Eurofins Ntd Llc |
RCV000078521 | SCV000110377 | pathogenic | not provided | 2014-07-22 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000078521 | SCV000239051 | pathogenic | not provided | 2022-08-13 | criteria provided, single submitter | clinical testing | Many individuals with c.441+5 G>T and another PAH variant were not found to be responsive to tetrahydrobiopterin (BH4), but data are still unclear (Zurfluh et al., 2008; Jeannesson-Thivisol et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 31355225, 24296287, 28676969, 9429153, 34426522, 31589614, 33101986, 32778825, 33465300, 33375644, 24941924, 23514811, 25087612, 26481238, 27121329, 26666653) |
Fulgent Genetics, |
RCV000150089 | SCV000611225 | pathogenic | Phenylketonuria | 2022-04-04 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000150089 | SCV000696449 | pathogenic | Phenylketonuria | 2016-09-29 | criteria provided, single submitter | clinical testing | Variant summary: The PAH c.441+5G>T variant involves the alteration of a conserved intronic nucleotide with 4/5 splice prediction tools predicting a significant impact on normal splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/121412 (1/24271), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126 (0.0079057). Multiple publications cite the variant in affected individuals who are homozygous and compound heterozygous, along with multiple databases/clinical diagnostic laboratories citing the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. |
Invitae | RCV000150089 | SCV000754087 | pathogenic | Phenylketonuria | 2024-01-16 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 4 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 (rs62507321, gnomAD 0.01%). This variant has been observed in individual(s) with phenylketonuria or hyperphenylalaninemia (PMID: 9429153, 17502162, 23514811, 23764561, 24296287, 24368688, 24941924, 25596310, 26666653). 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: 92742). 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. |
Ce |
RCV000078521 | SCV001250396 | pathogenic | not provided | 2023-12-01 | criteria provided, single submitter | clinical testing | PAH: PM3:Very Strong, PM2, PP4:Moderate, PP3 |
Revvity Omics, |
RCV000150089 | SCV002016496 | pathogenic | Phenylketonuria | 2021-10-18 | criteria provided, single submitter | clinical testing | |
3billion | RCV000150089 | SCV002058461 | pathogenic | Phenylketonuria | 2022-01-03 | criteria provided, single submitter | clinical testing | The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000092742). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (BioPKU, PS3_S). In silico prediction tools predicted that this variant influenced pre-mRNA splicing, resulting in aberrant splicing (SPLICEAI: 0.91>=0.8, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000032, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. |
Baylor Genetics | RCV000150089 | SCV004209565 | pathogenic | Phenylketonuria | 2023-10-02 | criteria provided, single submitter | clinical testing | |
Center for Genomic Medicine, |
RCV000150089 | SCV004804762 | pathogenic | Phenylketonuria | 2024-03-17 | criteria provided, single submitter | research | |
De |
RCV000078521 | SCV000119521 | not provided | not provided | no assertion provided | not provided | ||
Counsyl | RCV000150089 | SCV000791712 | pathogenic | Phenylketonuria | 2017-05-30 | no assertion criteria provided | clinical testing | |
Natera, |
RCV000150089 | SCV001455107 | pathogenic | Phenylketonuria | 2020-09-16 | no assertion criteria provided | clinical testing |