ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.806del (p.Ile269fs)

gnomAD frequency: 0.00002  dbSNP: rs62508687
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000153633 SCV000852125 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Extremely low frequency. gnomAD MAF=0.00007.; PP4: Detected in a PKU patient. BH4 deficiency not assessed. (PMID:9012412). 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, PM2, PP4).
Eurofins Ntd Llc (ga) RCV000089103 SCV000203181 pathogenic not provided 2017-06-14 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000153633 SCV000629216 pathogenic Phenylketonuria 2024-07-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ile269Thrfs*72) 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 (rs62508687, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with phenylketonuria (PMID: 9012412, 17502162, 18937047, 23430918, 24368688). This variant is also known as 1269fsdelT. ClinVar contains an entry for this variant (Variation ID: 102844). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000153633 SCV001361063 pathogenic Phenylketonuria 2019-06-06 criteria provided, single submitter clinical testing Variant summary: PAH c.806delT (p.Ile269ThrfsX72) 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 was absent in 251364 control chromosomes. c.806delT has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Tyfield_1997, Dombrowolski_2007, Sarkissian_2011, Ho_2013). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories and one expert panel (ClinGen) classify the variant as pathogenic three times and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000153633 SCV004209657 pathogenic Phenylketonuria 2023-11-21 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089103 SCV000119710 not provided not provided no assertion provided not provided
Counsyl RCV000153633 SCV000485936 likely pathogenic Phenylketonuria 2016-03-03 no assertion criteria provided clinical testing
Natera, Inc. RCV000153633 SCV001453103 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing

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