rs62642934
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3PM3PS3PP4_ModeratePM2
This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: MAF = 2.0e-5; PP3: Software agrees on a damaging effect.; PS3: Mutation ID#1, 18% residual enzyme activity (PMID:18590700); PM3: I306V / F55L (pathogenic in ClinVar) in a single patient with mild HPA (PMID:18299955); PP4_Moderate: BH4 defect excluded in all patients--single patient with mild hyperphe (Bercovich, 2008). (PMID:18299955). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4_Moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA114365/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.916A>G | p.Ile306Val | missense_variant | 9/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.916A>G | p.Ile306Val | missense_variant | 10/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.916A>G | p.Ile306Val | missense_variant | 9/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251236Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135772
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461056Hom.: 0 Cov.: 30 AF XY: 0.0000344 AC XY: 25AN XY: 726924
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74330
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 22, 2017 | Variant summary: The PAH c.916A>G (p.Ile306Val) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/121200 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant was reported in numerous individuals in the literature, mainly associated with mild-PKU or hyperphenylalaninemia. In addition, in vitro assays show the variant to result in reduced PAH activity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Aug 10, 2018 | PAH-specific ACMG/AMP criteria applied: PM2: MAF = 2.0e-5; PP3: Software agrees on a damaging effect.; PS3: Mutation ID#1, 18% residual enzyme activity (PMID:18590700); PM3: I306V / F55L (pathogenic in ClinVar) in a single patient with mild HPA (PMID:18299955); PP4_Moderate: BH4 defect excluded in all patients--single patient with mild hyperphe (Bercovich, 2008). (PMID:18299955). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4_Moderate). - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 26, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 21, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 306 of the PAH protein (p.Ile306Val). This variant is present in population databases (rs62642934, gnomAD 0.003%). This missense change has been observed in individuals with PAH-related disease (PMID: 1358789, 18299955, 23430547, 23764561). ClinVar contains an entry for this variant (Variation ID: 618). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 11161839, 17924342, 25596310). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2019 | - - |
Hyperphenylalaninemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1992 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at