rs199475687
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4PM4PM3PS3PM2
This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PP4: Phe>120 umol/L with PKU (PMID:25456745); PM3: In trans with: c.842+2T>A (P, ClinGen) (PMID:25456745); PS3: 0% in BioPKU; PM2: Extremely low frequency. ExAC MAF=0.00012; PM4: In frame deletion. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4, PM3, PS3, PM2, PM4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229490/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.208_210del | p.Ser70del | inframe_deletion | 3/13 | ENST00000553106.6 | |
LOC124902999 | XR_007063428.1 | n.863-9819_863-9817del | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.208_210del | p.Ser70del | inframe_deletion | 4/14 | ||
PAH | XM_017019370.2 | c.208_210del | p.Ser70del | inframe_deletion | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.208_210del | p.Ser70del | inframe_deletion | 3/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251342Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135842
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461628Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727132
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74410
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 17, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 07, 2021 | Variant summary: PAH c.208_210delTCT (p.Ser70del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein that is located in the ACT domain (IPR002912), which proposed to have a regulatory role in protein function (InterPro). The variant allele was found at a frequency of 1.2e-05 in 251342 control chromosomes (gnomAD). c.208_210delTCT has been reported in the literature in several compound heterozygous and homozygous individuals (mostly of East Asian origin) who were affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria), with reported disease phenotypes ranging from mild hyperphenylalaninemia to classic phenylketonuria (e.g. Okano_1998, Okano_2011, Zhu_2013, Tao_2015, Li_2018, Su_2019, Tao_2021); of note, in the 5 reported homozygous patients a mild PKU phenotype was described (Li_2018, Su_2019). 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. Four submitters, including an expert panel (ClinGen PAH Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 24, 2015 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Aug 05, 2018 | PAH-specific ACMG/AMP criteria applied: PP4: Phe>120 umol/L with PKU (PMID:25456745); PM3: In trans with: c.842+2T>A (P, ClinGen) (PMID:25456745); PS3: 0% in BioPKU; PM2: Extremely low frequency. ExAC MAF=0.00012; PM4: In frame deletion. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4, PM3, PS3, PM2, PM4). - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 26, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This variant, c.208_210del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Ser70del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs62642094, gnomAD 0.006%). This variant has been observed in individual(s) with PAH-related diseases from mild hyperphenylalaninemia to classic phenylketonuria (PMID: 15503242, 16256386, 23271928, 23932990; Invitae). ClinVar contains an entry for this variant (Variation ID: 102632). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. - |
not provided Other:3
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
not provided, flagged submission | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
not provided, flagged submission | 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