12-102855153-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP4_ModeratePP3PM3_Strong
This summary comes from the ClinGen Evidence Repository: The c.689T>C (p.Val230Ala) variant in PAH has been reported in multiple individuals with MHP, mild PKU and classical PKU (BH4 deficiency excluded, PMID:18299955, 29316886, 30747360). This variant is absent in population databases. This variant was detected with multiple pathogenic/likely pathogenic variants: p.V230I, p.A300S, and p.Arg243Gln (PMID:29316886). Computational evidence supports a deleterious effect. 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, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020840/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.689T>C | p.Val230Ala | missense_variant | Exon 6 of 13 | ENST00000553106.6 | NP_000268.1 | |
PAH | NM_001354304.2 | c.689T>C | p.Val230Ala | missense_variant | Exon 7 of 14 | NP_001341233.1 | ||
PAH | XM_017019370.2 | c.689T>C | p.Val230Ala | missense_variant | Exon 6 of 7 | XP_016874859.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.689T>C | p.Val230Ala | missense_variant | Exon 6 of 13 | 1 | NM_000277.3 | ENSP00000448059.1 | ||
PAH | ENST00000549111.5 | n.785T>C | non_coding_transcript_exon_variant | Exon 6 of 6 | 1 | |||||
PAH | ENST00000307000.7 | c.674T>C | p.Val225Ala | missense_variant | Exon 7 of 14 | 5 | ENSP00000303500.2 | |||
PAH | ENST00000551988.5 | n.*126T>C | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461754Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727208
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:3
- -
The c.689T>C (p.Val230Ala) variant in PAH has been reported in multiple individuals with MHP, mild PKU and classical PKU (BH4 deficiency excluded, PMID: 18299955, 29316886, 30747360). This variant is absent in population databases. This variant was detected with multiple pathogenic/likely pathogenic variants: p.V230I, p.A300S, and p.Arg243Gln (PMID: 29316886). Computational evidence supports a deleterious effect. 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, PP3. -
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at