rs62514904
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_000277.3(PAH):c.284_286del(p.Ile95del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. I95I) has been classified as Likely benign.
Frequency
Consequence
NM_000277.3 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.284_286del | p.Ile95del | inframe_deletion | 3/13 | ENST00000553106.6 | |
LOC124902999 | XR_007063428.1 | n.863-9892_863-9890del | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.284_286del | p.Ile95del | inframe_deletion | 4/14 | ||
PAH | XM_017019370.2 | c.284_286del | p.Ile95del | inframe_deletion | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.284_286del | p.Ile95del | inframe_deletion | 3/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251448Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135894
GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461828Hom.: 0 AF XY: 0.0000289 AC XY: 21AN XY: 727216
GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74360
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:10
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 16, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 06, 2023 | The p.Ile95del variant in PAH has been reported, in the homozygous and compound heterozygous state, in numerous (at least 10) individuals with PAH deficiency (phenylketonuria or hyperphenylalaninemia) (Li 2015 PMID: 26503515, Yan 2019 PMID: 30747360, Li 2008 PMID: 30050108, Schwoerer 2018 PMID: 29560316, Lee 2008 PMID: 18985011, Daniele 2009 PMID: 19292873, Ho 2014 PMID: 24368688, Chen 2015 PMID: 25894915, Jeannesson-Thivisol 2015 PMID: 26666653, Liu 2018 PMID: 29316886). It has also been classified as pathogenic on Oct 18, 2019 by the ClinGen PAH Variant Curation Expert Panel (Variation ID 604) and has been identified in 13/912 Amish and 5/68036 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). This variant is a deletion of 1 amino acid at position 95 and is not predicted to alter the protein reading-frame. In vitro functional studies support an impact on protein function as they show it results in a reduced affinity of the PAH enzyme for phenylalanine (Caillaud 1991 PMID: 1709636). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive phenylalanine hydroxylase (PAH) deficiency. ACMG/AMP criteria applied: PM3_Very strong, PM2_Supporting, PM4, PS3_Moderate. - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Oct 18, 2019 | This variant was documented in 8 patients diagnosed with PAH deficiency (PMID: 26503515, 30747360, 30050108, 29560316, 18985011). Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay. This variant was detected in trans with a pathogenic or likely pathogenic PAH variant in 2 patients with PKU and 3 patients with hyperphenylalaninemia (PMID: 19292873, 24368688, 25894915, 26666653, 29316886). This variant is present at a frequency below 0.0002 in the population databases ExAC and gnomAD. This variant changes protein length from an in-frame deletion in a non-repeat region. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM4, PP4_moderate. - |
Pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | The PAH c.284_286delTCA (p.I95del) variant results in a deletion of a single amino acid and has been observed in homozygous and compound heterozygous state in individuals with phenylketonuria. This variant has previously been shown to result in a reduced affinity of the PAH enzyme for phenylalanine (PMID: 1709636; 18985011; 19292873; 25894915; 26666653). - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | May 19, 2016 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 15, 2007 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 15, 2020 | Variant summary: PAH c.284_286delTCA (p.Ile95del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 251448 control chromosomes. c.284_286delTCA has been well reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Chien_2004, Daniele_2007, Caillaud_1991). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity (Maximal velocity/Km) due to a markedly decreased subtrate specificity (increased Km) for Phenylalanine (Caillaud_1991). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=4)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The observed inframe deletion variant c.284_286del (p.Ile95del) in PAH gene as been reported previously in multiple individuals affected with phenylketonuria (Schwoerer et al. 2018; Yan et al. 2019). In vitro expression studies showed that this variant produced very low levels of PAH activity (Caillaud et al. 1991; Li et al. 2015). The p.Ile95del variant is present with an allele frequency of 0.002% in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). This p.Ile95del causes deletion of amino acid Isoleucine at position 95. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This variant, c.284_286del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Ile95del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs62508727, gnomAD 0.006%). This variant has been observed in individual(s) with phenylketonuria and hyperphenylalaninemia (PMID: 1709636, 14722928, 17096675, 18985011, 19292873, 23430918, 25894915, 26666653). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Ile94del. ClinVar contains an entry for this variant (Variation ID: 604). 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. - |
not provided Pathogenic:3Other:2
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 06, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 16, 2020 | In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; Responsiveness to BH4 therapy is inconsistent (Zurfluh et al., 2008; Jeannesson-Thivisol et al., 2015); This variant is associated with the following publications: (PMID: 25894915, 19292873, 25255367, 14722928, 1709636, 17935162, 26503515, 24705691, 26666653, 19194782, 18985011, 17096675, 16256386, 24368688, 23430918, 20217238, 30487145, 31028937, 30747360, 32668217, 31589614, 32853555) - |
not provided, flagged submission | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at