rs199475565
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_000277.3(PAH):c.116_118del(p.Phe39del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000821 in 1,461,348 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
PAH
NM_000277.3 inframe_deletion
NM_000277.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.97
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000277.3
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000277.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
Variant 12-102912840-GAGA-G is Pathogenic according to our data. Variant chr12-102912840-GAGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 188933.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102912840-GAGA-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.116_118del | p.Phe39del | inframe_deletion | 2/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.116_118del | p.Phe39del | inframe_deletion | 3/14 | ||
PAH | XM_017019370.2 | c.116_118del | p.Phe39del | inframe_deletion | 2/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.116_118del | p.Phe39del | inframe_deletion | 2/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251412Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135874
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461348Hom.: 0 AF XY: 0.00000825 AC XY: 6AN XY: 726990
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Phenylketonuria Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 01, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Aug 22, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 22, 2024 | - - |
Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 23, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 23, 2018 | Variant summary: PAH c.116_118delTCT (p.Phe39del) results in an in-frame deletion that is predicted to remove a Phe amino acid from the encoded protein. The variant allele was found at a frequency of 1.6e-05 in 246172 control chromosomes. c.116_118delTCT has been reported in the literature in multiple individuals affected with classic and mild Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and mild hyperphenylalaninemia (Aldamiz-Echevarria_2016 and Zurfluh_2008). The variant was indicated to have 20% PAH enzyme activity (Zurfluh_2008). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites 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 | This c.113_115TCTdel (p.Phe39del) variant is also known as c.115_117delTTC (p.Phe39del) in the literature. This variant in PAH was reported in 3 Chinese patients with PAH deficiency (PMID: 26503515). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant was documented in 5 patients with PAH deficiency with a pathogenic or likely pathogenic variant in trans (PMID: 16256386, 23500595, 26542770, 29102225, 12655550). This variant is present in European (non-Finnish) populations at a frequency of 0.000035 (gnomAD), and in European (non-Finnish) populations at a frequency of 0.000045 (ExAC). This variant changes the protein length from an in-frame deletion in a non-repetitive region. Functional analysis of this variant found that it is associated with approximately 20% residual enzyme activity (PMID: 11161839; 17935162). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PP4_moderate, PM4, PS3-supporting, PM3_strong. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This variant, c.116_118del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Phe39del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs762462102, gnomAD 0.004%). This variant has been observed in individual(s) with phenylketonuria (PMID: 9452062, 12655550, 16256386, 19394257, 23500595, 26210745, 26542770). This variant is also known as DF39. ClinVar contains an entry for this variant (Variation ID: 188933). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the p.Phe39 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 206386, 8592329, 8659548, 12655544, 12655553, 17935162). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 13, 2023 | Published functional studies demonstrate a damaging effect on enzyme activity (Gjetting et al., 2001; Zurfluh et al, 2008); In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27121329, 26503515, 23430918, 34828281, 23500595, 17935162, 8406445, 18294361, 21147011, 28676969, 29499199, 34440436, 31589614, 32668217, 28182360, 35405047, 36246604, 11161839) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 30, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | PAH: PS4, PM2, PM3, PM4, PP4, PS3:Supporting - |
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at