12-102877548-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3PM3_StrongPP4_Moderate
This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PP3: in silico analysis supportive of damaging effect; PM3_Strong: In trans with R261Q (PMID 21147011), and in trans with IVS2+1G>A (PMID 12655554) (PMID:21147011; PMID:12655554); PP4_Moderate: BH4 deficiency excluded (PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PM3_Strong, PP4_Moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA220582/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.355C>T | p.Pro119Ser | missense_variant, splice_region_variant | 4/13 | ENST00000553106.6 | |
LOC124902999 | XR_007063428.1 | n.808-2331G>A | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.355C>T | p.Pro119Ser | missense_variant, splice_region_variant | 5/14 | ||
PAH | XM_017019370.2 | c.355C>T | p.Pro119Ser | missense_variant, splice_region_variant | 4/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.355C>T | p.Pro119Ser | missense_variant, splice_region_variant | 4/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000286 AC: 72AN: 251358Hom.: 0 AF XY: 0.000397 AC XY: 54AN XY: 135856
GnomAD4 exome AF: 0.000140 AC: 204AN: 1459698Hom.: 3 Cov.: 31 AF XY: 0.000204 AC XY: 148AN XY: 726300
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74460
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:7Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 04, 2023 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Jul 29, 2018 | PAH-specific ACMG/AMP criteria applied: PP3: in silico analysis supportive of damaging effect; PM3_Strong: In trans with R261Q (PMID 21147011), and in trans with IVS2+1G>A (PMID 12655554) (PMID:21147011; PMID:12655554); PP4_Moderate: BH4 deficiency excluded (PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PM3_Strong, PP4_Moderate). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Sep 10, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 25, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 119 of the PAH protein (p.Pro119Ser). This variant is present in population databases (rs398123292, gnomAD 0.2%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 12655554, 21147011, 30389586, 31355225). ClinVar contains an entry for this variant (Variation ID: 92741). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 | Feb 13, 2023 | Variant summary: PAH c.355C>T (p.Pro119Ser) results in a non-conservative amino acid change located in the 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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00029 in 251358 control chromosomes, predominantly at a frequency of 0.0023 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.00029 vs 0.0079), allowing no conclusion about variant significance. c.355C>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) or Hyperphenylalaninemia (e.g. Lindner_2003, Dobrowolski_2011, Esfahani_2018, Kuznetcova_2019, Su_2019). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic n=2, likely pathogenic n=5, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 26, 2021 | - - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 13, 2022 | 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: 15171997, 12655554, 34426522, 30389586, 32778825, 29771303, 21147011, 31355225) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 20, 2023 | This variant is associated with phenylketonuria and hyperphenylalaninemia (PMIDs: 17924342 (2007), 21147011 (20111), and 35405047 (2022)). The variant has been reported as homozygous (PMID: 36537053 (2022)) or compound heterozygous with other pathogenic PAH variants in multiple individuals with PAH-related conditions (PMIDs: 31355225 (2019), 30389586 (2019), and 32668217 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 24, 2017 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 06, 2023 | The c.355C>T (p.P119S) alteration is located in exon 4 (coding exon 4) of the PAH gene. This alteration results from a C to T substitution at nucleotide position 355, causing the proline (P) at amino acid position 119 to be replaced by a serine (S). Based on data from gnomAD, the T allele has an overall frequency of 0.029% (72/251358) total alleles studied. The highest observed frequency was 0.229% (70/30616) of South Asian alleles. This alteration has been reported compound heterozygous with a second alteration in PAH in multiple patients with biochemically confirmed PKU or hyperphenylalaninemia (Lindner, 2003; Esfahani, 2019; Su, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at