Submissions for variant NM_000277.3(PAH):c.842+2T>A

dbSNP: rs62514955

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000645	SCV001370843	pathogenic	Phenylketonuria	2020-04-16	reviewed by expert panel	curation	The c.842+2T>A variant in PAH is a splice-site variant predicted to result in skipping of exon 8, leading to a frameshift, premature protein truncation, and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It is reported Pathogenic in Clinvar (ID 614). It has been reported among multiple patients with classic PKU, with BH4 deficiency formally excluded (PMID: 17557229; PMID: 21307867) (PP4_Moderate) and has been reported in trans with multiple Pathogenic and Likely Pathogenic mutations, including R111X (P, ClinGen); P281L (P, ClinGen); R413P (P, ClinGen); R243Q (P, ClinGen); R261Q (LP/P, ClinGen); R400T (unknown, ClinGen) (PMID: 17557229) (PM3_Strong). Classification: Pathogenic Supporting Criteria: PVS1, PM2, PM3_Strong, PP4_Moderate
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000645	SCV001213687	pathogenic	Phenylketonuria	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individuals with phenylketonuria (PMID: 26322415, 27264808). This variant is also known as IVS7+2T>A. ClinVar contains an entry for this variant (Variation ID: 614). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000000645	SCV005053816	pathogenic	Phenylketonuria	2024-03-09	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000000645	SCV005417585	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PM3_VeryStrong+PP4
OMIM	RCV000000645	SCV000020795	pathogenic	Phenylketonuria	1989-11-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089131	SCV000119741	not provided	not provided		no assertion provided	not provided