ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.664_665del (p.Glu221_Asp222insTer)

dbSNP: rs62514936
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel 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, LabCorp 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 (formerly Invitae), Labcorp 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.
CeGaT Center for Human Genetics Tuebingen RCV000119778 SCV001249185 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing
Fulgent Genetics, 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, Mayo Clinic RCV000119778 SCV005414118 pathogenic not provided 2023-10-17 criteria provided, single submitter clinical testing PM2_moderate, PM3, PS3, PS4_moderate, PVS1
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000119778 SCV000119630 not provided not provided flagged submission not provided
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000119778 SCV000154685 not provided not provided no assertion provided not provided
Natera, Inc. RCV000169088 SCV002088650 pathogenic Phenylketonuria 2020-11-11 no assertion criteria provided clinical testing

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