chr12-102877457-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP4_ModeratePP3PS3PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.441+5G>T variant in PAH has been reported on >17 PKU alleles (BH4 deficiency excluded). (PP4_Moderate; PMID:17935162; PMID:23514811). This variant has an extremely low allele frequency (0.00002886) in gnomAD (PM2; http://gnomad.broadinstitute.org). This variant has 0% enzyme activity (PS3; http://www.biopku.org). This variant was detected in trans with IVS10-11g>a and p.V388M (Pathogenic in ClinVar) (PM3_Strong; PMID:23514811). Computational prediction tools and conservation analysis suggest that the c.441+5G>T variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Strong LINK:https://erepo.genome.network/evrepo/ui/classification/CA273112/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

PAH
NM_000277.3 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:16O:1

Conservation

PhyloP100: 7.28

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:

LOC124902999 (HGNC:):

LOC124902999 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.441+5G>T	splice_region_variant, intron_variant	Intron 4 of 12	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.441+5G>T	splice_region_variant, intron_variant	Intron 5 of 13		NP_001341233.1
PAH	XM_017019370.2 link	c.441+5G>T	splice_region_variant, intron_variant	Intron 4 of 6		XP_016874859.1
LOC124902999	XR_007063428.1 link	n.808-2422C>A	intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.441+5G>T		splice_region_variant, intron_variant	Intron 4 of 12	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251488

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1458196

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

725660

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000473

Hom.:

Bravo

AF:

0.0000793

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:11

Oct 18, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 30, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 24, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000092742). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (BioPKU, PS3_S). In silico prediction tools predicted that this variant influenced pre-mRNA splicing, resulting in aberrant splicing (SPLICEAI: 0.91>=0.8, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000032, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jun 30, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.441+5G>T variant in PAH has been reported in at least 20 individuals with phenylalanine hydroxylase deficiency including at least 12 compound heterozygotes (Zurflüh 2008 PMID: 17935162, Bueno 2013 PMID: 23514811), several of whom presented with classical phenylketonuria (PKU). It has also been identified in 0.0065% (1/15282) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar as pathogenic by the ClinGen PAH Variant Curation Expert Panel using the . ACMG-AMP criteria specific for phenylalanine hydroxylase variants (Zastrow 2018 PMID: 30311390) and is curated in the FDA-recognized human genetic variant database (Variation ID 102784). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function and decreases PAH activity to 0% (Bueno 2013 PMID: 23514811); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive phenylalanine hydroxylase deficiency. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PP4_Moderate, PM3_VeryStrong, PS3 -

May 24, 2018

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.441+5G>T variant in PAH has been reported on >17 PKU alleles (BH4 deficiency excluded). (PP4_Moderate; PMID: 17935162; PMID: 23514811). This variant has an extremely low allele frequency (0.00002886) in gnomAD (PM2; http://gnomad.broadinstitute.org). This variant has 0% enzyme activity (PS3; http://www.biopku.org). This variant was detected in trans with IVS10-11g>a and p.V388M (Pathogenic in ClinVar) (PM3_Strong; PMID: 23514811). Computational prediction tools and conservation analysis suggest that the c.441+5G>T variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Strong -

Sep 29, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PAH c.441+5G>T variant involves the alteration of a conserved intronic nucleotide with 4/5 splice prediction tools predicting a significant impact on normal splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/121412 (1/24271), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126 (0.0079057). Multiple publications cite the variant in affected individuals who are homozygous and compound heterozygous, along with multiple databases/clinical diagnostic laboratories citing the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 4 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 (rs62507321, gnomAD 0.01%). This variant has been observed in individual(s) with phenylketonuria or hyperphenylalaninemia (PMID: 9429153, 17502162, 23514811, 23764561, 24296287, 24368688, 24941924, 25596310, 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: 92742). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. -

Apr 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:4Other:1

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PAH: PM3:Very Strong, PM2, PP4:Moderate, PP3 -

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 22, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 13, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Many individuals with c.441+5 G>T and another PAH variant were not found to be responsive to tetrahydrobiopterin (BH4), but data are still unclear (Zurfluh et al., 2008; Jeannesson-Thivisol et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 31355225, 24296287, 28676969, 9429153, 34426522, 31589614, 33101986, 32778825, 33465300, 33375644, 24941924, 23514811, 25087612, 26481238, 27121329, 26666653) -

Sep 03, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2_moderate, PM3_strong, PS3 -

PAH-related disorder

Pathogenic:1

Jun 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PAH c.441+5G>T variant is predicted to interfere with splicing. This variant, which lies near the junction of exon 4 and intron 4 and is predicted to disrupt splicing, has been reported as causative in either the homozygous or compound heterozygous state for phenylalanine hydroxylase deficiency (see for example Zekanowski et al. 1997. PubMed ID: 9429153; Bueno et al. 2013. PubMed ID: 23514811; Trunzo et al. 2013. PubMed ID: 24296287; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). Other variants within the same splice site region (e.g., c.441+1G>A,c.441+2T>G, c.441+3G>C, c.441+6T>A) have been reported with a second PAH variant in individuals with phenylalanine hydroxylase deficiency (see for example Table S3 in Hillert et al. 2020. PubMed ID: 32668217). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD. This variant has been classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel as well as multiple other submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/92742/). Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.91

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.91

Position offset: 5

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