ClinVar Miner

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

dbSNP: rs199475697
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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 RCV000587795 SCV004015326 pathogenic Phenylketonuria 2023-03-16 reviewed by expert panel curation The c.592_613del (p.Tyr198fs) variant in PAH is a frameshift variant predicted to cause termination at amino acid 334 in exon 10, resulting in nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. It has been detected in multiple patients with PAH deficiency with pathogenic variants: c.782G>A (p.Arg261Gln) (PMID: 21890392); c.1222C>T (p.Arg408Trp) (PMID:26481238); c.969+1G>A (IVS9 + 1G>A) (PMID:18321666); c.311C>A (p.A104D), c.755G>A (p.R252Q) (PMID:23942198). This variant is absent in population databases. In summary, this variant meets criteria to be classified as Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PM3_strong, PP4_moderate, PVS1
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 2023-05-23 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 102746). This premature translational stop signal has been observed in individual(s) with phenylketonuria or hyperphenylalaninemia (PMID: 9359039, 21890392, 24301756). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs199475697, gnomAD 0.01%). 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. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000088995 SCV001823930 pathogenic not provided 2019-11-26 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 at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21147011, 8069318, 19292873, 28676969, 24301756, 17096675, 26701937, 22572109, 10767174)
Ambry Genetics RCV002514544 SCV003586357 pathogenic Inborn genetic diseases 2021-12-21 criteria provided, single submitter clinical testing The c.592_613del22 (p.Y198Sfs*136) alteration, located in exon 6 (coding exon 6) of the PAH gene, consists of a deletion of 22 nucleotides from position 592 to 613, causing a translational frameshift with a predicted alternate stop codon after 136 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation has been reported in the homozygous state and in trans with a second alteration in patients with phenylalanine hydroxylase deficiency (Daniele, 2009; Kostandyan, 2011; Ajami, 2013; Carducci, 2020). Based on the available evidence, this alteration is classified as pathogenic.
3billion RCV000587795 SCV003841329 pathogenic Phenylketonuria 2023-02-23 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 26481238). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000102746). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000587795 SCV003924229 pathogenic Phenylketonuria 2021-03-30 criteria provided, single submitter clinical testing PAH NM_000277.2 exon 6 p.Tyr198Serfs*136 (c.592_613del): This variant has been reported in the literature in the homozygous state in two individuals with phenylketonuria (Daniele 2009 PMID:19292873, Ajami 2013 PMID:24301756) and has been reported in the PAH Consortium Database (www.biopku.org). This variant is present in 0.01% (5/35428) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-103249006-TCATAGCAAGCATGGGTTTTATA-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar (Variation ID:102746). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents a deletion of 22 nucleotides and creates a premature stop codon 136 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene (Eisensmith 1992 PMID:1301187, Guldberg 1998 PMID:9634518). In summary, this variant is classified as pathogenic based on the data above.
Baylor Genetics RCV000587795 SCV004209646 pathogenic Phenylketonuria 2023-07-06 criteria provided, single submitter clinical testing
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
Natera, Inc. RCV000587795 SCV002088657 pathogenic Phenylketonuria 2020-08-20 no assertion criteria provided clinical testing

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