Submissions for variant NM_000277.3(PAH):c.1038del (p.Leu347fs)

dbSNP: rs62516063

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000780556	SCV002032232	pathogenic	Phenylketonuria	2021-10-10	reviewed by expert panel	curation	The c.1038del (p.Leu347fs) variant in PAH has been reported in a Danish PKU patient, serum Phe >600 umol/L; BH4 deficiency excluded (PMID: 8406445; PP4). This frameshift variant is predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 10 out of 13 coding exons (10 out of total exons) (PVS1). 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, PM2, PP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780556	SCV000917923	pathogenic	Phenylketonuria	2018-05-17	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1038delG (p.Leu347SerfsX53) 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 (eg. c.1055delG/p.Gly352fsX48, c.1089delG/p.Lys363fsX37). The variant was absent in 246240 control chromosomes. c.1038delG has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and mild HPA depending on the second allele. These data indicate that the variant is associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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	RCV000780556	SCV002238586	pathogenic	Phenylketonuria	2021-09-26	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 102487). This sequence change creates a premature translational stop signal (p.Leu347Serfs*53) 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 (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with hyperphenylalaninemia (PMID: 8406445). This variant is also known as 346delG. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088718	SCV000119298	not provided	not provided		no assertion provided	not provided