ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.398_401del (p.Asn133fs)

dbSNP: rs199475605
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000531628 SCV002818522 pathogenic Phenylketonuria 2022-10-14 reviewed by expert panel curation This c.398_401del (p.Asn133fs) variant in PAH was detected with pathogenic and likely pathogenic variants in multiple patients with classic PKU and one with mild hyperphenylalaninemia (PMID: 22513348, 22526846, 8659548, 22917871, 26666653). This variant was absent in population databases. This is a frameshift variant in exon 4 of 13 predicted to undergo nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_Strong, PP4_moderate.
Labcorp Genetics (formerly Invitae), Labcorp RCV000531628 SCV000629191 pathogenic Phenylketonuria 2024-03-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn133Argfs*61) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PKU) (PMID: 10429004, 23430918, 26666653). ClinVar contains an entry for this variant (Variation ID: 102663). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000531628 SCV000788569 pathogenic Phenylketonuria 2017-01-24 criteria provided, single submitter clinical testing
GeneDx RCV000088910 SCV001790344 pathogenic not provided 2023-02-22 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10429004, 23430918, 22513348, 27869385, 26666653, 32668217)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000531628 SCV002600846 pathogenic Phenylketonuria 2022-10-31 criteria provided, single submitter clinical testing Variant summary: PAH c.398_401delATCA (p.Asn133ArgfsX61) 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 251466 control chromosomes (gnomAD). c.398_401delATCA has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Guldberg_1996, Groselj_2012). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000531628 SCV004201367 pathogenic Phenylketonuria 2023-10-16 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088910 SCV000119508 not provided not provided no assertion provided not provided

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