rs62516141
Variant summary
Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3PM3PM2PP4_Moderate
This summary comes from the ClinGen Evidence Repository: The c.1157A>G (p.Tyr386Cys) variant in PAH has been reported in multiple probands with PKU (BH4 deficiency excluded) (PMID:16198137; PP4_Moderate). This variant has been detected with c.1315+1G>A, R252W, L311P, R261Q, I65V, Q178G, R158Q (all reported as Pathogenic in ClinVar, 4.0 points total) (PMIDs:24368688, 24941924, 22841515, 16198137, 26210745, 23357515, 18493213; PM3_very-strong). This variant is absent from population databases (PM2) and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.975 (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274152/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.1157A>G | p.Tyr386Cys | missense_variant | 11/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.1157A>G | p.Tyr386Cys | missense_variant | 12/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.1157A>G | p.Tyr386Cys | missense_variant | 11/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152066Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251290Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135802
GnomAD4 exome AF: 0.0000677 AC: 99AN: 1461616Hom.: 0 Cov.: 30 AF XY: 0.0000619 AC XY: 45AN XY: 727108
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152066Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74298
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 10, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 386 of the PAH protein (p.Tyr386Cys). This variant is present in population databases (rs62516141, gnomAD 0.004%). This missense change has been observed in individual(s) with phenylketonuria or hyperphenylalaninemia (PMID: 16198137, 16765994, 22841515, 23430918, 24350308, 24368688). ClinVar contains an entry for this variant (Variation ID: 102538). 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 expected to disrupt PAH protein function. This variant disrupts the p.Tyr386 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 23430918), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 26, 2018 | Variant summary: PAH c.1157A>G (p.Tyr386Cys) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 246044 control chromosomes (gnomAD). c.1157A>G has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)(Bayat_2016, Trunzo_2015, Ho_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Aug 22, 2014 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | May 15, 2021 | The c.1157A>G (p.Tyr386Cys) variant in PAH has been reported in multiple probands with PKU (BH4 deficiency excluded) (PMID: 16198137; PP4_Moderate). This variant has been detected with c.1315+1G>A, R252W, L311P, R261Q, I65V, Q178G, R158Q (all reported as Pathogenic in ClinVar, 4.0 points total) (PMIDs:24368688, 24941924, 22841515, 16198137, 26210745, 23357515, 18493213; PM3_very-strong). This variant is absent from population databases (PM2) and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.975 (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 14, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 13, 2023 | - - |
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 | GeneDx | Jun 29, 2020 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24941924, 24350308, 16765994, 22841515, 17924342, 29499199, 25087612, 26210745, 8533759, 11385716, 23357515, 11696894, 24368688, 23430918, 12655553, 23074961, 10394930, 9634518, 18493213, 16198137, 32668217) - |
Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Undiagnosed Diseases Network, NIH | Oct 27, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at