Submissions for variant NM_000277.3(PAH):c.1066-3C>T

gnomAD frequency: 0.00002  dbSNP: rs62507344

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000654	SCV004222617	pathogenic	Phenylketonuria	2023-12-30	reviewed by expert panel	curation	The c.1066-3C>T variant in PAH has been reported in multiple individuals with Classic PKU and MHP (BH4 deficiency excluded). (PMID: 9634518, 27121329). It has been detected with multiple pathogenic variants: c.1222C>T (p.Arg408Trp) (in trans, PMID: 27121329); c.1315+1G>A (PMID: 17502162); p.G272X, p.S310F (PMID: 23430918); c.194T>C (p.I65T), c.1208C>T (p.A403V), c.398_401del (p.N133fs), c.1222C>T (p.R408W) 2 patients, c.165delT (p.F55fs), c.168+5G>C (IVS2+5G>C) (PMID: 22526846). This variant has an extremely low allele frequency in ExAC and gnomAD (MAF=0.00014). This variant has 0% enzyme activity. This variant resulted in the skipping of exon 11 with the premature termination of RNA translation downstream from exon 12 (PMID: 8098245). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PP4_Moderate, PM2_supporting.
Counsyl	RCV000000654	SCV000220862	likely pathogenic	Phenylketonuria	2014-11-06	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000088742	SCV000225209	pathogenic	not provided	2014-11-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000654	SCV000836557	pathogenic	Phenylketonuria	2024-10-22	criteria provided, single submitter	clinical testing	This sequence change falls in intron 10 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs62507344, gnomAD 0.02%). This variant has been observed in individual(s) with mild hyperphenylalaninemia and phenylketonuria (PMID: 8098245, 17502162, 19444284, 22526846, 22698810, 23357515, 24368688, 26666653). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 623). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 8098245, 22698810). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000000654	SCV000914555	pathogenic	Phenylketonuria	2018-12-18	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the PAH c.1066-3C>T splice region variant has been reported in at least six studies in which it is found in a total of 15 probands including one in a homozygous state and 14 in a compound heterozygous state (Abadie et al. 1993; Dobrowolski et al. 2009; Heintz et al. 2012; Sterl et al. 2013; Ho et al. 2014; Jeannesson-Thivisol et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00019 in the European (Finnish) population of the Genome Aggregation Database. Liver biopsy from a compound heterozygous proband found 1.5% of normal PAH activity (Abadie et al. 1993). RT-PCR of proband derived lymphoblast cells indicated exon 11 skipping and COS-1 cells transfected with minigenes confirmed c.1066-3C>T as the cause of exon 11 skipping (Heintz et al. 2012). Based on the evidence, the c.1066-3C>T variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000654	SCV001362284	pathogenic	Phenylketonuria	2019-05-13	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1066-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 3' acceptor site and two predict the variant weakens a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing leading to exon 11 skipping (Heintz_2012). The variant allele was found at a frequency of 4e-05 in 250904 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (4e-05 vs 0.0079), allowing no conclusion about variant significance. c.1066-3C>T has been reported in the literature in multiple individuals affected with Phenylketonuria and Hyperphenylalaninemia (Heintz_2012, Reblova_2013, Sterl_2013). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000088742	SCV001822273	pathogenic	not provided	2020-01-06	criteria provided, single submitter	clinical testing	Published in vitro study demonstrates the c.1066-3C>T variant results in skipping of exon 11 (Abadie et al., 1993); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Responsiveness to tetrahydrobiopterin (BH4) therapy is not clear (Sarkissian et al., 2012); This variant is associated with the following publications: (PMID: 33101986, 32668217, 31589614, 22526846, 8098245, 29288420, 26666653, 24368688, 7657610, 15464430, 22513348, 21147011, 22698810, 22841515, 23430918, 23672685)
Baylor Genetics	RCV000000654	SCV004201381	pathogenic	Phenylketonuria	2024-03-30	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000000654	SCV005051907	pathogenic	Phenylketonuria	2024-02-01	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV000088742	SCV005414104	pathogenic	not provided	2024-09-03	criteria provided, single submitter	clinical testing	PP4_moderate, PM2, PM3_very_strong
OMIM	RCV000000654	SCV000020804	pathogenic	Phenylketonuria	1993-01-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088742	SCV000119325	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000000654	SCV002088631	pathogenic	Phenylketonuria	2021-02-19	no assertion criteria provided	clinical testing