rs62517205
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM3_StrongPP4_ModeratePM2
This summary comes from the ClinGen Evidence Repository: The c.601C>T (p.His201Tyr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID:16198137). This variant is at a ow frequency in controls (3.964e-6 in gnomAD; PM2). This variant was detected with known pathogenic variants IVS10nt546 (PMID:9521426) and R158Q (PMID:16198137; PM3_strong). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229643/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.601C>T | p.His201Tyr | missense_variant | 6/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.601C>T | p.His201Tyr | missense_variant | 7/14 | ||
PAH | XM_017019370.2 | c.601C>T | p.His201Tyr | missense_variant | 6/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.601C>T | p.His201Tyr | missense_variant | 6/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000549111.5 | n.697C>T | non_coding_transcript_exon_variant | 6/6 | 1 | ||||
PAH | ENST00000307000.7 | c.586C>T | p.His196Tyr | missense_variant | 7/14 | 5 | |||
PAH | ENST00000551988.5 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251344Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135832
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461740Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4AN XY: 727174
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 201 of the PAH protein (p.His201Tyr). This variant is present in population databases (rs62517205, gnomAD 0.0009%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 9521426, 10598814, 16198137, 23792259). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102752). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Mar 15, 2017 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Nov 10, 2019 | The c.601C>T (p.His201Tyr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 16198137). This variant is at a ow frequency in controls (3.964e-6 in gnomAD; PM2). This variant was detected with known pathogenic variants IVS10nt546 (PMID: 9521426) and R158Q (PMID: 16198137; PM3_strong). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 18, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
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 | May 03, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23357515, 23792259, 10598814, 35023679, 32668217, 9521426, 16198137) - |
Hyperphenylalaninemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 13, 2017 | Variant summary: The PAH c.601C>T (p.His201Tyr) variant located in the Aromatic amino acid hydroxylase, C-terminal (via InterPro) involves the alteration of a conserved nucleotide and 3/5 in silico tools predict a damaging outcome. Reblova_2013 indicates that the His201 plays a key role in forming a H-bond needed for stablization. This variant is absent in 121300 control chromosomes (ExAC). Multiple publications have cited the variant in affected compound heterozygote individuals, predominantly from Italy, with a mild HPA. Taken together, the variant of interest has been classified as "pathogenic." - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at