Submissions for variant NM_000277.3(PAH):c.822_832del (p.Lys274fs)

dbSNP: rs199475581

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001200000	SCV001370852	pathogenic	Phenylketonuria	2020-04-05	reviewed by expert panel	curation	The c.822_832delGCCCATGTATA (p.Lys274Asnfs) variant in PAH is a null variant (frameshift variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at an extremely low frequency in gnomAD (MAF = 0.00000398, less than the 0.0002 MAF cutoff) and absent from other ethnically diverse control databases, including 1000 Genomes and ESP (PM2). It has been previously reported in Clinvar (variation ID 102852) without any classification. It has been previously reported in at least 7 cases with PKU (confirmed by abnormal blood Phe levels) in whom BH4 deficiency was excluded (PP4_Moderate); it has also been noted in one case with hyperphenyalanemia. As detailed below, it has been found in confirmed trans with multiple known pathogenic variants (e.g., p.R408W, p.R261Q, p.F39del, p.A104D) in six probands total and in trans with a VUS (p.T81P variant) in one case (PM3_VeryStrong). These reports are as follows. It has been previously found in two unrelated German probands with classic PKU (determined by blood Phe levels); BH4 deficiency does not appear to have been formally excluded (PMID: 1363786). The two unrelated patients in this report (PMID: 1363786) were each confirmed compound heterozygotes: one carried it in trans with the known pathogenic p.R408W allele and the other carried it in trans with the known pathogenic p.R261Q allele (these two variants have been classified pathogenic per PAH VCEP). It has also been identified in two unrelated European PKU cases in whom BH4 deficiency was said to be excluded, each of whom were confirmed compound heterozygous for the variant with the known pathogenic p.R408Q allele (PMID: 24190797). In another report, it was found in confirmed trans in three white European cases in whom BH4 deficiency was said to be excluded and who presented with classic PKU by blood Phe levels: one case with the c.115_117delTTC (p.F39del) variant (Pathogenic per PAH VCEP), one case with the p.T81P variant (VUS per PAH VCEP), and one case with the p.A104D variant (Pathogenic per PAH VCEP) (PMID: 23430918). It has also been noted in a cohort of Czech patients with hyperphenylalanemia, but further detail does not appear to be provided (PMID: 23357515). Classification: Pathogenic Supporting criteria: PVS1, PM2, PM3_VeryStrong, PP4_Moderate
Invitae	RCV001200000	SCV001590186	pathogenic	Phenylketonuria	2023-02-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys274Asnfs*5) 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 present in population databases (rs199475581, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with hyperphenylalaninemia (PMID: 1363786, 17935162, 23357515). This variant is also known as c.1043del11. ClinVar contains an entry for this variant (Variation ID: 102852). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001200000	SCV002570565	pathogenic	Phenylketonuria	2022-07-14	criteria provided, single submitter	clinical testing	Variant summary: PAH c.822_832del11 (p.Lys274AsnfsX5) 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 allele was found at a frequency of 4e-06 in 251320 control chromosomes (gnomAD). c.822_832del11 has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Zschocke_1999, Dobrowolski_2009, Sarkissian_2012). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters including an expert panel (ClinGen PAH Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000089113	SCV002765715	pathogenic	not provided	2022-06-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 32668217, 1363786)
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089113	SCV000119720	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV001200000	SCV002088640	pathogenic	Phenylketonuria	2020-08-27	no assertion criteria provided	clinical testing