chr12-102839172-GCTTTA-G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2_SupportingPM3_StrongPM4PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1357_*2delTAAAG (p.Ter453Profs) variant in PAH has been reported in multiple individuals with PAH deficiency; one with other causes of hyperphenylalninemia ruled out with panel sequencing. (PP4_Moderate; PMID:10679941, data share with Invitae). This variant is at low frequency in population databases (TopMed AF=0.00001). This variant was detected with known pathogenic/likely pathogenic variants: p.L48 (unknown phase, PMID:10679941); c.1066-11G>A, p.Arg408Trp, p.Arg155Pro, (unknown phase, PMID:32668217); and Leu348Val (in trans, data share with Invitae). The deletion p.Ter453Profs is predicted to abolish the stop codon and causes an elongation of the polypeptide by 35 amino acids (PM4). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM2-supporting, PM3_strong, PM4. LINK:https://erepo.genome.network/evrepo/ui/classification/CV194161/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PAH
NM_000277.3 frameshift, stop_lost

Scores

Not classified

Clinical Significance

Likely pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 6.97

Publications

1 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PM4
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 HGVSp Effect Exon rank MANE Protein UniProt
PAHNM_000277.3 linkc.1357_*2delTAAAG p.Ter453fs frameshift_variant, stop_lost Exon 13 of 13 ENST00000553106.6 NP_000268.1 P00439A0A024RBG4
PAHNM_000277.3 linkc.1357_*2delTAAAG 3_prime_UTR_variant Exon 13 of 13 ENST00000553106.6 NP_000268.1 P00439A0A024RBG4
PAHNM_001354304.2 linkc.1357_*2delTAAAG p.Ter453fs frameshift_variant, stop_lost Exon 14 of 14 NP_001341233.1
PAHNM_001354304.2 linkc.1357_*2delTAAAG 3_prime_UTR_variant Exon 14 of 14 NP_001341233.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAHENST00000553106.6 linkc.1357_*2delTAAAG p.Ter453fs frameshift_variant, stop_lost Exon 13 of 13 1 NM_000277.3 ENSP00000448059.1 P00439
PAHENST00000553106.6 linkc.1357_*2delTAAAG 3_prime_UTR_variant Exon 13 of 13 1 NM_000277.3 ENSP00000448059.1 P00439

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152146
Hom.:
0
Cov.:
33
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1460874
Hom.:
0
AF XY:
0.00000413
AC XY:
3
AN XY:
726764
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33454
American (AMR)
AF:
0.00
AC:
0
AN:
44704
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26128
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39688
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86226
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53328
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1111222
Other (OTH)
AF:
0.00
AC:
0
AN:
60358
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.438
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152146
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74314
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41436
American (AMR)
AF:
0.00
AC:
0
AN:
15268
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:5
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Phenylketonuria Pathogenic:3
Oct 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change disrupts the translational stop signal of the PAH mRNA. It is expected to extend the length of the PAH protein by 33 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This protein extension has been observed in individual(s) with PAH-related conditions (PMID: 10679941; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Feb 10, 2024
Baylor Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 23, 2023
ClinGen PAH Variant Curation Expert Panel
Significance:Likely pathogenic
Review Status:reviewed by expert panel
Collection Method:curation

The c.1357_*2delTAAAG (p.Ter453Profs) variant in PAH has been reported in multiple individuals with PAH deficiency; one with other causes of hyperphenylalninemia ruled out with panel sequencing. (PP4_Moderate; PMID: 10679941, data share with Invitae). This variant is at low frequency in population databases (TopMed AF=0.00001). This variant was detected with known pathogenic/likely pathogenic variants: p.L48 (unknown phase, PMID: 10679941); c.1066-11G>A, p.Arg408Trp, p.Arg155Pro, (unknown phase, PMID: 32668217); and Leu348Val (in trans, data share with Invitae). The deletion p.Ter453Profs is predicted to abolish the stop codon and causes an elongation of the polypeptide by 35 amino acids (PM4). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM2-supporting, PM3_strong, PM4. -

not provided Pathogenic:2
Feb 02, 2015
Eurofins Ntd Llc (ga)
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 12, 2025
GeneDx
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Stop codon loss and change to a Proline codon, leading to protein extension and the addition of 33 amino acid(s) at the C-terminus; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10679941, 32668217) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
7.0
Mutation Taster
=79/21
disease causing (ClinVar)

Splicing

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

Publications

Other links and lift over

dbSNP: rs794727086; hg19: chr12-103232950; API