ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.806del (p.Ile269fs) (rs62508687)

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Total submissions: 6
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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).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000089103 SCV000203181 pathogenic not provided 2017-06-14 criteria provided, single submitter clinical testing
Invitae RCV000153633 SCV000629216 pathogenic Phenylketonuria 2017-05-02 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 7 of the PAH mRNA (c.806delT), causing a frameshift at codon 269. This creates a premature translational stop signal (p.Ile269Thrfs*72) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic. This particular variant has been reported as homozygous or compound heterozygous in multiple individuals affected with phenylketonuria (PMID: 9012412, 17502162, 23430918, 24368688, 18937047). This variant is also known as 1269fsdelT in the literature. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America 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.
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

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