ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.592_613del (p.Tyr198fs) (rs199475697)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587795 SCV000696457 pathogenic Phenylketonuria 2016-01-21 criteria provided, single submitter clinical testing Variant summary: This c.592_613del22 variant causes a frameshift, which alters the proteins amino acid sequence beginning at position 198 and leads to a premature termination codon 136 amino acids downstream. It is predicted to cause a truncated or absent PAH protein. Loss-of-function due to mutations in this gene is an established disease mechanism in Phenylketoneuria. This variant was not found in approximately 121322 chromosomes from the broad and large populations of ExAC. This variant has been recurrently reported as a causative mutation in patients with Phenylketoneuria. The region this variant is located is a mutational hot-spot where other similar pathogenic frameshift variants (such as c.586del22, c.589del22, c.590del23 and c.593del22) (source: HGMD) have been reported. Reputable databases have also classified this variant as pathogenic. Taken together, this variant has been classified as a Pathogenic.
Invitae RCV000587795 SCV001209421 pathogenic Phenylketonuria 2020-06-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr198Serfs*136) in the PAH gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals with phenylketonuria or hyperphenylalaninemia (PMID: 24301756, 21890392, 9359039). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102746). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088995 SCV000119599 not provided not provided no assertion provided not provided
Counsyl RCV000587795 SCV001132446 likely pathogenic Phenylketonuria 2014-02-25 no assertion criteria provided clinical testing

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