Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000277.2(PAH):c.830A>G (p.Tyr277Cys)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229800

102860 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 159e0913-0a8e-4eef-9a1d-2cd35121aaca

Approved on: 2020-06-08

Published on: 2021-09-06

HGVS expressions

NM_000277.2:c.830A>G

NM_000277.2(PAH):c.830A>G (p.Tyr277Cys)

NC_000012.12:g.102852827T>C

CM000674.2:g.102852827T>C

NC_000012.11:g.103246605T>C

CM000674.1:g.103246605T>C

NC_000012.10:g.101770735T>C

NG_008690.1:g.69776A>G

NG_008690.2:g.110584A>G

ENST00000553106.6:c.830A>G

ENST00000307000.7:c.815A>G

ENST00000549247.6:n.589A>G

ENST00000553106.5:c.830A>G

NM_000277.1:c.830A>G

NM_001354304.1:c.830A>G

NM_000277.3:c.830A>G

NM_001354304.2:c.830A>G

Pathogenic

PP4 PP3 PM5 PM2 PM3_Strong

BP2

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.830A>G (p.Tyr277Cys) variant in PAH has been reported in multiple individuals with PKU (PMID:24350308). This variant has an extremely low allele frequency (MAF=0.00006) in gnomAD. It was detected with multiple pathogenic variants: p.R408W in 2 patients; p.L194P (PMID: 24350308); c.842+1G>A in 2 patients (PMID: 25952249). Computational prediction tools and conservation analysis support a deleterious effect. Another missense change at the same amino acid (p.Y277D), is pathogenic by 8 submitters. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP3, PP4

PP4

Found in 3 individuals with PKU. BH4 deficiency not reportedly ruled out. PMID: 24350308

Found in individual with PKU but in cis with V245A and in trans with IVS12+1G>A. PubMed:16601866

PP3

Predicted deleterious by MutationTaster, Polyphen, and SIFT.

PM5

Y277D, pathogenic in Clinvar (Var ID=603) 8 submitters

PM2

Low freq found in gnomAD (MAF=0.00006) Absent in 1000 Genomes and ESP.

PM3_Strong

detected with p.R408W (P 14 submitters) in 2 patients; p.L194P(c.581T>C) LP PAH VCEP parental analysis not reported PMID: 24350308; c.842+1G>A in 2 patients (P 3 submitters) PMID: 25952249 parental analysis not reported 2.25 pts

BP2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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