rs62517166

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM3_SupportingPVS1PP4_ModeratePM2

This summary comes from the ClinGen Evidence Repository: The c.441+1G>C variant in PAH is a canonical splice-site variant predicted to result in skipping of exon 5, leading to a frameshift, premature protein truncation, and NMD (PVS1). It is present at an extremely low frequency in gnomAD (MAF = 0.00000398, less than the 0.0002 MAF cutoff) (PM2) and absent from other ethnically diverse control databases, including 1000 Genomes and ESP (PM2). It is reported Likely Pathogenic in Clinvar (Variation ID 556894) by one diagnostic testing lab. It has been reported in the published literature in a Kurdish patient with classic PKU (PMID:24048906), diagnosed by plasma Phe levels; BH4 deficiency was excluded by urinary pterin analysis (PP4_Moderate). The patient was homozygous for the variant (PMID:24048906) (PM3_Supporting). Classification: PathogenicSupporting Criteria: PVS1, PM2, PM3_Supporting, PP4_Moderate LINK:https://erepo.genome.network/evrepo/ui/classification/CA6748955/MONDO:0009861/006

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PAH
NM_000277.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: 7.28

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

phenylketonuria
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
classic phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
maternal phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild hyperphenylalaninemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PAH links:

LOC124902999 (HGNC:):

LOC124902999 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PVS1

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.

PP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
PAH	NM_000277.3 link	c.441+1G>C	splice_donor_variant, intron_variant	Intron 4 of 12	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 link	c.441+1G>C	splice_donor_variant, intron_variant	Intron 5 of 13		NP_001341233.1
PAH	XM_017019370.2 link	c.441+1G>C	splice_donor_variant, intron_variant	Intron 4 of 6		XP_016874859.1
LOC124902999	XR_007063428.1 link	n.808-2418C>G	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+1G>C		splice_donor_variant, intron_variant	Intron 4 of 12	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251482

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459438

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109766

Other (OTH)

AF:

0.00

AC:

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:3

Mar 22, 2025

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 05, 2020

ClinGen PAH Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.441+1G>C variant in PAH is a canonical splice-site variant predicted to result in skipping of exon 5, leading to a frameshift, premature protein truncation, and NMD (PVS1). It is present at an extremely low frequency in gnomAD (MAF = 0.00000398, less than the 0.0002 MAF cutoff) (PM2) and absent from other ethnically diverse control databases, including 1000 Genomes and ESP (PM2). It is reported Likely Pathogenic in Clinvar (Variation ID 556894) by one diagnostic testing lab. It has been reported in the published literature in a Kurdish patient with classic PKU (PMID: 24048906), diagnosed by plasma Phe levels; BH4 deficiency was excluded by urinary pterin analysis (PP4_Moderate). The patient was homozygous for the variant (PMID: 24048906) (PM3_Supporting). Classification: Pathogenic Supporting Criteria: PVS1, PM2, PM3_Supporting, PP4_Moderate -

Feb 26, 2018

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Uncertain

0.95

PhyloP100

7.3

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.91

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.91

Position offset: 1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over