Submissions for variant NM_000277.3(PAH):c.398_401del (p.Asn133fs)

dbSNP: rs199475605

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000531628	SCV002818522	pathogenic	Phenylketonuria	2022-10-14	reviewed by expert panel	curation	This c.398_401del (p.Asn133fs) variant in PAH was detected with pathogenic and likely pathogenic variants in multiple patients with classic PKU and one with mild hyperphenylalaninemia (PMID: 22513348, 22526846, 8659548, 22917871, 26666653). This variant was absent in population databases. This is a frameshift variant in exon 4 of 13 predicted to undergo nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_Strong, PP4_moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531628	SCV000629191	pathogenic	Phenylketonuria	2024-03-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn133Argfs*61) 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 (PKU) (PMID: 10429004, 23430918, 26666653). ClinVar contains an entry for this variant (Variation ID: 102663). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000531628	SCV000788569	pathogenic	Phenylketonuria	2017-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000088910	SCV001790344	pathogenic	not provided	2023-02-22	criteria provided, single submitter	clinical testing	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; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10429004, 23430918, 22513348, 27869385, 26666653, 32668217)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000531628	SCV002600846	pathogenic	Phenylketonuria	2022-10-31	criteria provided, single submitter	clinical testing	Variant summary: PAH c.398_401delATCA (p.Asn133ArgfsX61) 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 251466 control chromosomes (gnomAD). c.398_401delATCA has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Guldberg_1996, Groselj_2012). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000531628	SCV004201367	pathogenic	Phenylketonuria	2023-10-16	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088910	SCV000119508	not provided	not provided		no assertion provided	not provided