rs5030849
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000277.3(PAH):c.782G>T(p.Arg261Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R261G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.782G>T | p.Arg261Leu | missense_variant | 7/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.782G>T | p.Arg261Leu | missense_variant | 8/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.782G>T | p.Arg261Leu | missense_variant | 7/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000307000.7 | c.767G>T | p.Arg256Leu | missense_variant | 8/14 | 5 | |||
PAH | ENST00000549247.6 | n.541G>T | non_coding_transcript_exon_variant | 1/6 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:1Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Nov 08, 2019 | The c.782G>T (p.Arg261Leu) variant in PAH has been previously reported Pathogenic by one clinical laboratory in ClinVar (see variant ID 576255); the laboratory stated that it was found as an "inherited" allele in 1 Han Chinese proband with PKU (subtype not otherwise specified, no further phenotypic details given). No further information regarding zygosity, familial segregation, and/or functional assays was provided, and no formal classification criteria were given, aside from "case-control" was given in the collection method. The variant results in a substitution of a highly conserved Arg residue with Leucine; the two amino acid residues are physiochemically distinct (basic versus nonpolar side chains) and the substitution is predicted damaging by multiple lines of computational evidence, e.g., Predicted deleterious in SIFT, Polyphen2, Mutation Taster. REVEL= 0.979) (PP3). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). [Although there is frequency data retrieved for it in the PAGE/GGV browser in the ClinGen VCI, when the genomic coordinates for it are entered into the browser, nothing comes up]. Other missense changes at this Arg (Arg261) have been previously reported Pathogenic or Likely Pathogenic in ClinVar, e.g., p.Arg261Gln (Pathogenic per internal PAH ClinGen Working Group classification, ClinVar ID 582), as well as p.Arg261Gly and p.Arg261Pro (PM5). - |
Pathogenic, no assertion criteria provided | case-control | Clinical Laboratory, Xuzhou Maternity and Child Health Care Hospital | Jun 26, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at