Submissions for variant NM_000277.3(PAH):c.58C>T (p.Gln20Ter)

dbSNP: rs199475585

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000169450	SCV001146739	pathogenic	Phenylketonuria	2019-02-26	reviewed by expert panel	curation	Pathogenic: The c.58C>T (p.Gln20Ter) is a null variant reported in one patient with classic PKU phenotype (PVS1, PP4, PMID: 9391881). This variant is absent from population databases, including gnomAD, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4.
Counsyl	RCV000169450	SCV000220871	likely pathogenic	Phenylketonuria	2014-11-12	criteria provided, single submitter	literature only
CeGaT Center for Human Genetics Tuebingen	RCV000088993	SCV001250403	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169450	SCV001370580	pathogenic	Phenylketonuria	2020-05-25	criteria provided, single submitter	clinical testing	Variant summary: PAH c.58C>T (p.Gln20X) 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 251430 control chromosomes. c.58C>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Kozak_1997, Guldberg_1998, Quirk_2012, Djordjevic_2013, Polak_2013, Reblova_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory and one expert panel (ClinGen) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169450	SCV001400667	pathogenic	Phenylketonuria	2024-05-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln20*) 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 individuals with phenylketonuria (PKU) (PMID: 9391881, 23357515, 23430547, 23764561, 27121329). ClinVar contains an entry for this variant (Variation ID: 102744). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000088993	SCV002512913	pathogenic	not provided	2021-05-24	criteria provided, single submitter	clinical testing	Reported in multiple individuals with classic phenylketonuria (PKU) or mild hyperphenylalaninemia (HPA) in the presence of a second pathogenic variant (Stojiljkovic et al., 2006; Quirk et al., 2012); Nonsense 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 significant frequency in large population cohorts (gnomAD); Responsiveness to BH4 therapy is unclear (Djordjevic et al., 2013); This variant is associated with the following publications: (PMID: 23357515, 27121329, 1301187, 25525159, 9284280, 9391881, 23764561, 23430547, 9634518, 16879198, 22841515, 32668217)
Baylor Genetics	RCV000169450	SCV005053825	pathogenic	Phenylketonuria	2024-02-21	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088993	SCV000119597	not provided	not provided		no assertion provided	not provided