Submissions for variant NM_000277.3(PAH):c.664_665del (p.Glu221_Asp222insTer)

dbSNP: rs62514936

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000169088	SCV004222611	pathogenic	Phenylketonuria	2023-12-30	reviewed by expert panel	curation	The c.664_665del (p.Asp222Ter) variant in PAH is a nonsense variant in exon 6 of 13, with nonsense mediated decay predicted to occur (PVS1). This variant was detected in at least one patient with mild PKU where BH4 deficiency was excluded by analysis of neopterin and biopterin in urine and measurement of dihydropteridine reductase activity in dried blood spots (PMID:16290003, PP4_moderate). It was found to co-occur (phase unknown) with the pathogenic variant IVS10-3C>T (PM3_supporting). This deletion has a MAF of 0.00003874 in the European (non-Finnish) population in GnomAD v2.1.1 (PM2_supporting). Therefore this variant is classified as Pathogenic by the PAH VCEP; PAH-specific ACMG/AMP criteria applied: PVS1, PP4_moderate, PM2_supporting, PM3_supporting.
Counsyl	RCV000169088	SCV000220265	likely pathogenic	Phenylketonuria	2014-04-23	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169088	SCV000917933	pathogenic	Phenylketonuria	2018-12-20	criteria provided, single submitter	clinical testing	Variant summary: PAH c.664_665delGA (p.Asp222X) 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. The variant allele was found at a frequency of 1.8e-05 in 277080 control chromosomes (gnomAD). c.664_665delGA has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) with limited residual activity <10% (Bayat_2016, Zurfluh_2008). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169088	SCV000937953	pathogenic	Phenylketonuria	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp222*) 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 (rs759154440, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PMID: 18937047, 24350308, 26666653). ClinVar contains an entry for this variant (Variation ID: 133249). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000119778	SCV001249185	pathogenic	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169088	SCV002805786	pathogenic	Phenylketonuria	2021-07-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169088	SCV004209593	pathogenic	Phenylketonuria	2023-12-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000119778	SCV005414118	pathogenic	not provided	2023-10-17	criteria provided, single submitter	clinical testing	PM2_moderate, PM3, PS3, PS4_moderate, PVS1
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000119778	SCV000119630	not provided	not provided		flagged submission	not provided
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000119778	SCV000154685	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000169088	SCV002088650	pathogenic	Phenylketonuria	2020-11-11	no assertion criteria provided	clinical testing