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]

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Variant: NM_000277.3(PAH):c.527G>A (p.Arg176Gln)

CA229606

102724 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 02d09d57-cc20-48ba-a7ba-a52c7dbc8cd2

HGVS expressions

NM_000277.3:c.527G>A

NM_000277.3(PAH):c.527G>A (p.Arg176Gln)

NM_000277.1:c.527G>A

NM_000277.2:c.527G>A

NM_001354304.1:c.527G>A

NM_001354304.2:c.527G>A

ENST00000307000.7:c.512G>A

ENST00000549111.5:n.623G>A

ENST00000551988.5:n.548G>A

ENST00000553106.5:c.527G>A

NC_000012.12:g.102855315C>T

CM000674.2:g.102855315C>T

NC_000012.11:g.103249093C>T

CM000674.1:g.103249093C>T

NC_000012.10:g.101773223C>T

NG_008690.1:g.67288G>A

NG_008690.2:g.108096G>A

Pathogenic

PM2 PM5 PP4_Moderate PM3_Strong

PP3

Evidence Links 4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.527G>A (p.Arg176Gln) variant in PAH was reported in at least two patients with PAH deficiency (PMID: 30459323, 26210745, and 27121329) and detected with pathogenic variants p.Val388Met, p.Arg158Gln, and Arg243Gln (PMID: 27121329,10234516, and 30459323). This variant has extremely low frequency in gnomAD (MAF=0.00007). One other missense variant at this amino acid residue is determined to be pathogenic in ClinVar: p.Arg176Leu by nine submitters. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific AMCG/AMP criteria applied: PM3_strong, PM2, PM5, and PP4_moderate.

PM2

Variant identified in 2/30614 South Asian chromosomes (MAF=0.00007) in gnomAD.

PM5

One other missense variant at this amino acid residue is determined to be pathogenic in ClinVar: p.Arg176Leu by nine submitters.

PP4_Moderate

This variant was observed in at least two probands with mild HPA and one proband with mild PKU. Phe > 120 µmol/L in all probands described. 6R-BH4 was ruled out by urinary pterin levels and by measuring dihydropteridine reductase activity in at least one article. PMID: 30459323, 26210745, and 27121329

PubMed:26210745

PubMed:30459323

PubMed:27121329

PM3_Strong

p.[Arg176Gln];[Val388Met], [R176Q/R158Q], and p.[R243Q];[R176Q]. Segregation analysis was done in all cases. PMID: 27121329,10234516, and 30459323

PubMed:10234516

PP3

Prediction models disagree. SIFT predicts damaging, PolyPhen2 predicts benign, and MutationTaster predicts neutral.

Approved on: 2020-10-15

Published on: 2020-10-15

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