rs118203925
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.140C>T (p.Ala47Val) variant in PAH has been reported in 3 individuals with MHP (BH4 deficiency excluded). (PMID:24368688, 27121329). This variant has extremely low frequency in gnomAD MAF=0.00001. This variant was detected with pathogenic variants p.E280K (parental analysis not reported), p.Glu178Gly, c.1066-11G>A (segregation analysis done). 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/CA114370/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.140C>T | p.Ala47Val | missense_variant | 2/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.140C>T | p.Ala47Val | missense_variant | 3/14 | ||
PAH | XM_017019370.2 | c.140C>T | p.Ala47Val | missense_variant | 2/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.140C>T | p.Ala47Val | missense_variant | 2/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251412Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135874
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1460924Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6AN XY: 726800
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74352
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 10, 2023 | Variant summary: PAH c.140C>T (p.Ala47Val) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251412 control chromosomes (gnomAD). c.140C>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and -mild hyperphenylalaninemia (examples: Aldamiz-Echevarria_2016, Bayat_2016, Ho_2013). These data indicate that the variant is likely to be associated with disease. Experimental studies have shown that this missense change affects PAH function (examples: Gjetting_MGM_2001, Gjetting_AJHG_2001, and Himmelreich_2018). The following publications have been ascertained in the context of this evaluation (PMID: 11161839, 11326337, 30037505, 27121329, 24368688, and 26542770). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | May 22, 2020 | The c.140C>T (p.Ala47Val) variant in PAH has been reported in 3 individuals with MHP (BH4 deficiency excluded). (PMID: 24368688, 27121329). This variant has extremely low frequency in gnomAD MAF=0.00001. This variant was detected with pathogenic variants p.E280K (parental analysis not reported), p.Glu178Gly, c.1066-11G>A (segregation analysis done). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 47 of the PAH protein (p.Ala47Val). This variant is present in population databases (rs118203925, gnomAD 0.0009%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 24368688, 27121329). ClinVar contains an entry for this variant (Variation ID: 630). 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, 11326337, 17924342, 27121329). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 18, 2024 | - - |
Hyperphenylalaninemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 15, 1994 | - - |
not provided Other:1
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