Submissions for variant NM_000277.3(PAH):c.722del (p.Arg241fs)

dbSNP: rs199475657

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000169560	SCV001370813	pathogenic	Phenylketonuria	2020-05-09	reviewed by expert panel	curation	The PAH variant c.722del (p.Arg241fs) is a null variant (frameshift indel) located in exon number 7 of the PAH gene. The loss of function in the PAH gene is a mechanism of disease: 98 pathogenic null variants were reported in ClinVar for this gene, across 13 different exons, of which 11 variants were found on exon 7. The mRNA transcript is predicted to undergo NMD. The PAH variant c.722del (p.Arg241fs) was detected in four Chinese patients with classic PKU (Phe levels >20 mg/dl) and one Chinese patient with mild PKU (Phe levels 10-20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 26322415). The variant c.722del (p.Arg241fs) was detected in trans (confirmed by parental DNA analyses) in five Chinese patients with the following PAH pathogenic variants: c.498C>G (p.Tyr166Ter) (ClinVar ID: 371373), c.728G>A (p.Arg243Gln) (ClinVar ID: 591), and c.1223G>A (p.Arg408Gln) (ClinVar ID: 612) (PMID: 26322415). The variant c.722del (p.Arg241fs) was also detected in three compound heterozygous Chinese patients with the following PAH pathogenic and likely pathogenic variants: c.611A>G (p.Tyr204Cys) (ClinVar ID: 590), c.1223G>A (p.Arg408Gln) (ClinVar ID: 612)(PMID: 30459323). PM3_Very Strong (6.75). The variant c.722del (p.Arg241fs) is absent from the gnomAD, and ExAC population databases. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Very Strong (6.75), PVS1, PP4_Moderate.
Counsyl	RCV000169560	SCV000221055	likely pathogenic	Phenylketonuria	2015-01-21	criteria provided, single submitter	literature only
Invitae	RCV000169560	SCV001222077	pathogenic	Phenylketonuria	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg241Profs*100) 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 individual(s) with phenylketonuria (PMID: 12905706, 25550961, 29499199). This variant is also known as p.Arg241fs or p.Arg241fsX5. ClinVar contains an entry for this variant (Variation ID: 102806). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169560	SCV002556002	pathogenic	Phenylketonuria	2022-06-20	criteria provided, single submitter	clinical testing	Variant summary: PAH c.722delG (p.Arg241ProfsX100) 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 251030 control chromosomes (gnomAD). c.722delG has been reported in the literature in several Chinese individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Tao_2015, Li_2018, Wang_2018). 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. Three submitters, including an expert panel (ClinGen PAH Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=2; including the Expert Panel) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000169560	SCV004209612	pathogenic	Phenylketonuria	2023-08-22	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089057	SCV000119662	not provided	not provided		no assertion provided	not provided