Total submissions: 16
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000000641 | SCV000852174 | pathogenic | Phenylketonuria | 2018-08-05 | reviewed by expert panel | curation | PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PP4: Detected in 2 unrelated patients (PMID:1682234); PM3: Detected with H170D, pathogenic (PMID:11385716). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PP4, PM3). |
Eurofins Ntd Llc |
RCV000089090 | SCV000232040 | pathogenic | not provided | 2015-02-23 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000089090 | SCV000581840 | pathogenic | not provided | 2020-11-17 | criteria provided, single submitter | clinical testing | Functional analysis found that R261X is associated with significantly reduced enzyme activity (Zurflh et al., 2008; Ho et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Classified as not responsive to tetrahydrobiopterin (BH4) therapy (Zurflh et al., 2008); This variant is associated with the following publications: (PMID: 30747360, 25525159, 12655553, 10693064, 23500595, 17935162, 24401910, 1682234, 23532445, 28676969, 15503242, 19062537, 30067850, 29499199, 30221392, 31355225, 30275481, 31589614, 33101986) |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000000641 | SCV000919918 | pathogenic | Phenylketonuria | 2018-08-03 | criteria provided, single submitter | clinical testing | Variant summary: PAH c.781C>T (p.Arg261X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.2e-05 in 277050 control chromosomes. c.781C>T has been reported in the literature in numerous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Zurfluh_2008). 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Invitae | RCV000000641 | SCV001215251 | pathogenic | Phenylketonuria | 2023-11-03 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg261*) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs5030850, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with PAH-related conditions (PMID: 30067850). ClinVar contains an entry for this variant (Variation ID: 610). 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 |
RCV000089090 | SCV001249181 | pathogenic | not provided | 2019-01-01 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV000000641 | SCV001810236 | pathogenic | Phenylketonuria | 2021-07-22 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000000641 | SCV002016497 | pathogenic | Phenylketonuria | 2019-04-11 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000089090 | SCV002046336 | pathogenic | not provided | 2020-11-12 | criteria provided, single submitter | clinical testing | This nonsense variant causes the premature termination of PAH protein synthesis. In addition, it has been reported in multiple classic and mild PKU patients in the published literature (PMID: 16601866 (2006), 16755493 (2006), 19394257 (2009), 20920871 (2011), 22841515 (2012), 30067850 (2018)). Therefore, the variant is classified as pathogenic. |
Cellular and Molecular Medicine Research Institute, |
RCV000000641 | SCV004035242 | pathogenic | Phenylketonuria | 2023-09-19 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000000641 | SCV004209584 | pathogenic | Phenylketonuria | 2023-09-15 | criteria provided, single submitter | clinical testing | |
Center for Genomic Medicine, |
RCV003984798 | SCV004801189 | pathogenic | Pulmonary hypertension, primary, 1 | 2024-03-14 | criteria provided, single submitter | research | |
OMIM | RCV000000641 | SCV000020791 | pathogenic | Phenylketonuria | 1991-10-01 | no assertion criteria provided | literature only | |
De |
RCV000089090 | SCV000119696 | not provided | not provided | no assertion provided | not provided | ||
Counsyl | RCV000000641 | SCV000485311 | pathogenic | Phenylketonuria | 2016-01-21 | no assertion criteria provided | clinical testing | |
Natera, |
RCV000000641 | SCV001453106 | pathogenic | Phenylketonuria | 2020-09-16 | no assertion criteria provided | clinical testing |