Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000411734 | SCV000886618 | pathogenic | Phenylketonuria | 2018-12-09 | reviewed by expert panel | curation | The c.632delC (p.Pro211Hisfs) variant in PAH leads to a frameshift at amino acid 211/432. It is identified with low frequency in population databases (1.648e-5). It has been identified in two individuals with Phenylketonuria as a homozygous variant and in trans with c.1066-11G>A (PMID: 26413448; 26666653). It has been described in multiple patients with PKU, although a defect in BH4 metabolism has not been excluded as a cause of elevated phenylalanine in any case. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. |
Counsyl | RCV000411734 | SCV000486031 | pathogenic | Phenylketonuria | 2016-03-17 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000411734 | SCV001426895 | pathogenic | Phenylketonuria | 2020-07-30 | criteria provided, single submitter | clinical testing | Variant summary: PAH c.632delC (p.Pro211HisfsX130) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251336 control chromosomes. c.632delC has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Jeannesson-Thivisol_2015, Biglari_2015, Guldberg_1996). These data indicate that the variant is likely to be associated with disease. At least one publication reports indirect experimental evidence as having been identified in homozygosity in a patient with a confirmed biochemical, enzymatic and clinical diagnosis of classic PAH (example, Biglari_2015). One clinical diagnostic laboratory and one expert panel (ClinGen PAH Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Labcorp Genetics |
RCV000411734 | SCV002228974 | pathogenic | Phenylketonuria | 2024-01-12 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Pro211Hisfs*130) 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 (rs62514929, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of hyperphenylalaninemia (PMID: 8659548, 26413448). ClinVar contains an entry for this variant (Variation ID: 102767). For these reasons, this variant has been classified as Pathogenic. |
Baylor Genetics | RCV000411734 | SCV004201973 | pathogenic | Phenylketonuria | 2022-08-05 | criteria provided, single submitter | clinical testing | |
De |
RCV000089017 | SCV000119621 | not provided | not provided | no assertion provided | not provided | ||
Natera, |
RCV000411734 | SCV002088653 | pathogenic | Phenylketonuria | 2019-12-14 | no assertion criteria provided | clinical testing |