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.1031G>A (p.Gly344Asp)

Curation Version - 1.0
Curation History
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CA229288

102481 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 916728eb-a8f7-4a52-852e-9a7b866bade4

Approved on: 2021-06-11

Published on: 2021-06-11

HGVS expressions

NM_000277.2:c.1031G>A

NM_000277.2(PAH):c.1031G>A (p.Gly344Asp)

NC_000012.12:g.102844370C>T

CM000674.2:g.102844370C>T

NC_000012.11:g.103238148C>T

CM000674.1:g.103238148C>T

NC_000012.10:g.101762278C>T

NG_008690.1:g.78233G>A

NG_008690.2:g.119041G>A

ENST00000553106.6:c.1031G>A

ENST00000307000.7:c.1016G>A

ENST00000549247.6:n.790G>A

ENST00000551114.2:n.693G>A

ENST00000553106.5:c.1031G>A

ENST00000635477.1:n.135G>A

ENST00000635528.1:n.546G>A

NM_000277.1:c.1031G>A

NM_001354304.1:c.1031G>A

NM_000277.3:c.1031G>A

NM_001354304.2:c.1031G>A

Likely Pathogenic

PP4_Moderate PM2 PP3 PM3_Strong

PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1031G>A (p.Gly344Asp) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 26503515). This variant is absent in population databases. This variant was detected in with multiple pathogenic variants: p.Arg241Cys (PMID: 18985011); p.R252Q (PMID: 26322415); EX6-96A＞G (PMID: 29316886); p.Q232* (PMID: 30050108). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3.

PP4_Moderate

Seen in 2 individuals with PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. PMID: 26503515

PM2

Absent from controls in ExAC, 1000 Genomes, gnomAD.

PP3

Deleterious effect predicted by SIFT, PolyPhen, and MutationTaster

PM3_Strong

Detected with p.Arg241Cys (blood samples were collected from the patients and their family members) PMID: 18985011; p.[R252Q];[G344D]; confirmed by analyzing parental DNA. PMID: 26322415; EX6-96A＞G; (variable sites in patient were aligned with the corresponding sites from the respective parents). PMID: 29316886; p.G344D/p.Q232* (validated on parents) PMID: 30050108 3.5 points

PM5

G334V curated as likely pathogenic, US in ClinVar.

Curation History

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