rs62507347
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000277.3(PAH):āc.227A>Gā(p.Glu76Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E76A) has been classified as Pathogenic.
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.227A>G | p.Glu76Gly | missense_variant | 3/13 | ENST00000553106.6 | |
LOC124902999 | XR_007063428.1 | n.863-9838T>C | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.227A>G | p.Glu76Gly | missense_variant | 4/14 | ||
PAH | XM_017019370.2 | c.227A>G | p.Glu76Gly | missense_variant | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.227A>G | p.Glu76Gly | missense_variant | 3/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461576Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727112
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 08, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 11, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 76 of the PAH protein (p.Glu76Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PKU, and hyperphenylalaninemia or mild hyperphenylalaninemia (PMID: 11935335, 12655546, 24401910; Invitae). 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: 639). 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. Experimental studies have shown that this missense change affects PAH function (PMID: 17935162, 21953985). 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 | Eurofins Ntd Llc (ga) | Jul 03, 2017 | - - |
Hyperphenylalaninemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2002 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at