Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000169088 | SCV004222611 | pathogenic | Phenylketonuria | 2023-12-30 | reviewed by expert panel | curation | The c.664_665del (p.Asp222Ter) variant in PAH is a nonsense variant in exon 6 of 13, with nonsense mediated decay predicted to occur (PVS1). This variant was detected in at least one patient with mild PKU where BH4 deficiency was excluded by analysis of neopterin and biopterin in urine and measurement of dihydropteridine reductase activity in dried blood spots (PMID:16290003, PP4_moderate). It was found to co-occur (phase unknown) with the pathogenic variant IVS10-3C>T (PM3_supporting). This deletion has a MAF of 0.00003874 in the European (non-Finnish) population in GnomAD v2.1.1 (PM2_supporting). Therefore this variant is classified as Pathogenic by the PAH VCEP; PAH-specific ACMG/AMP criteria applied: PVS1, PP4_moderate, PM2_supporting, PM3_supporting. |
Counsyl | RCV000169088 | SCV000220265 | likely pathogenic | Phenylketonuria | 2014-04-23 | criteria provided, single submitter | literature only | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000169088 | SCV000917933 | pathogenic | Phenylketonuria | 2018-12-20 | criteria provided, single submitter | clinical testing | Variant summary: PAH c.664_665delGA (p.Asp222X) 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 1.8e-05 in 277080 control chromosomes (gnomAD). c.664_665delGA has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) with limited residual activity <10% (Bayat_2016, Zurfluh_2008). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. |
Labcorp Genetics |
RCV000169088 | SCV000937953 | pathogenic | Phenylketonuria | 2025-01-07 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Asp222*) 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 (rs759154440, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PMID: 18937047, 24350308, 26666653). ClinVar contains an entry for this variant (Variation ID: 133249). 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 |
RCV000119778 | SCV001249185 | pathogenic | not provided | 2019-07-01 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000169088 | SCV002805786 | pathogenic | Phenylketonuria | 2021-07-07 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000169088 | SCV004209593 | pathogenic | Phenylketonuria | 2023-12-27 | criteria provided, single submitter | clinical testing | |
Mayo Clinic Laboratories, |
RCV000119778 | SCV005414118 | pathogenic | not provided | 2023-10-17 | criteria provided, single submitter | clinical testing | PM2_moderate, PM3, PS3, PS4_moderate, PVS1 |
De |
RCV000119778 | SCV000119630 | not provided | not provided | flagged submission | not provided | ||
De |
RCV000119778 | SCV000154685 | not provided | not provided | no assertion provided | not provided | ||
Natera, |
RCV000169088 | SCV002088650 | pathogenic | Phenylketonuria | 2020-11-11 | no assertion criteria provided | clinical testing |