rs62507344

Positions:

chr12-102843782-G-A

Variant summary

Our verdict is Pathogenic. Variant got 5 ACMG points: 5P and 0B. PP4_ModeratePM3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229324/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

PAH
NM_000277.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.1155

Clinical Significance

Pathogenic reviewed by expert panel P:11O:1

Conservation

PhyloP100: 3.60

Variant links:

Genes affected

PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

PAH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 5 ACMG points.

PM2

PM3

PP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.1066-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000553106.6
PAH	NM_001354304.2 linkuse as main transcript	c.1066-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.1066-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000277.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000399

AC:

AN:

250904

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135626

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000547

AC:

AN:

1461280

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

726984

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000207

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:9

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 13, 2019	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. -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Dec 30, 2023	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. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Nov 06, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 19, 2021	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 18, 2018	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. -

not provided

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2020	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) -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 06, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.12

dbscSNV1_RF

Benign

0.45

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over