Submissions for variant NM_000277.3(PAH):c.1198del (p.Arg400fs)

dbSNP: rs199475590

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000671992	SCV001762317	pathogenic	Phenylketonuria	2021-05-29	reviewed by expert panel	curation	The c.1198del (p.Arg400fs) variant in PAH has been detected in 1 patient from the Northeastern US, serum Phe > 240umol/L; BH4 deficiency not excluded (PMID: 8659548; PP4). This variant was detected with c.168+1G>A and I65T, both reported as pathogenic in ClinVar and confirmed in trans (2.0points; PM3_Strong). This frameshift variant is not predicted to undergo NMD, located in intron 11-12 out of 13 total exons (11 out of total exons) (PVS1_Strong), and this variant is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1_Strong, PM2, PP4, PM3_Strong.
Counsyl	RCV000671992	SCV000797042	pathogenic	Phenylketonuria	2018-01-09	criteria provided, single submitter	clinical testing
Invitae	RCV000671992	SCV001204166	pathogenic	Phenylketonuria	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg400Glyfs*52) in the PAH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the PAH protein. This variant is present in population databases (rs199475590, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PMID: 7726156). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 1197/1198delA, R400fsdelA. ClinVar contains an entry for this variant (Variation ID: 102554). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg408 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1312992, 2014036, 10471838, 12173030, 24401910, 29317692). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000671992	SCV001361068	pathogenic	Phenylketonuria	2019-07-22	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1198delA (p.Arg400GlyfsX52) 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 4e-06 in 251264 control chromosomes (gnomAD). The variant, c.1198delA, has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Eiken_1996, Guldberg_1996, Ramus_1995). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submission (evaluation after 2014) classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic
Baylor Genetics	RCV000671992	SCV004201337	pathogenic	Phenylketonuria	2023-10-25	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088788	SCV000119375	not provided	not provided		no assertion provided	not provided