Submissions for variant NM_000277.3(PAH):c.632del (p.Pro211fs)

dbSNP: rs62514929

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000411734	SCV000886618	pathogenic	Phenylketonuria	2018-12-09	reviewed by expert panel	curation	The c.632delC (p.Pro211Hisfs) variant in PAH leads to a frameshift at amino acid 211/432. It is identified with low frequency in population databases (1.648e-5). It has been identified in two individuals with Phenylketonuria as a homozygous variant and in trans with c.1066-11G>A (PMID: 26413448; 26666653). It has been described in multiple patients with PKU, although a defect in BH4 metabolism has not been excluded as a cause of elevated phenylalanine in any case. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4.
Counsyl	RCV000411734	SCV000486031	pathogenic	Phenylketonuria	2016-03-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411734	SCV001426895	pathogenic	Phenylketonuria	2020-07-30	criteria provided, single submitter	clinical testing	Variant summary: PAH c.632delC (p.Pro211HisfsX130) 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 8e-06 in 251336 control chromosomes. c.632delC has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Jeannesson-Thivisol_2015, Biglari_2015, Guldberg_1996). These data indicate that the variant is likely to be associated with disease. At least one publication reports indirect experimental evidence as having been identified in homozygosity in a patient with a confirmed biochemical, enzymatic and clinical diagnosis of classic PAH (example, Biglari_2015). One clinical diagnostic laboratory and one expert panel (ClinGen PAH Variant Curation Expert Panel) 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.
Invitae	RCV000411734	SCV002228974	pathogenic	Phenylketonuria	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro211Hisfs*130) 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 (rs62514929, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of hyperphenylalaninemia (PMID: 8659548, 26413448). ClinVar contains an entry for this variant (Variation ID: 102767). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000411734	SCV004201973	pathogenic	Phenylketonuria	2022-08-05	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089017	SCV000119621	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000411734	SCV002088653	pathogenic	Phenylketonuria	2019-12-14	no assertion criteria provided	clinical testing