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.1102G>A (p.Glu368Lys)

CA386493305

625289 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f131a516-cf1e-4b4c-b85d-6ab00c72ed7b

HGVS expressions

NM_000277.3:c.1102G>A

NM_000277.3(PAH):c.1102G>A (p.Glu368Lys)

NM_000277.1:c.1102G>A

NM_000277.2:c.1102G>A

NM_001354304.1:c.1102G>A

NM_001354304.2:c.1102G>A

ENST00000307000.7:c.1087G>A

ENST00000549247.6:n.861G>A

ENST00000551114.2:n.764G>A

ENST00000553106.5:c.1102G>A

ENST00000635477.1:n.206G>A

ENST00000635528.1:n.617G>A

NC_000012.12:g.102843743C>T

CM000674.2:g.102843743C>T

NC_000012.11:g.103237521C>T

CM000674.1:g.103237521C>T

NC_000012.10:g.101761651C>T

NG_008690.1:g.78860G>A

NG_008690.2:g.119668G>A

Likely Pathogenic

PM3 PM2 PP4_Moderate

PP3 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.1102G>A (p.Glu368Lys) variant in PAH has been reported in 1 individual with moderate PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 31355225). This variant has extremely low frequency in gnomAD: MAF=0.00001 (PM2). This variant was detected in trans with pathogenic variant c.1066-11G>A. Parents were also investigated to confirm their carrier status. (PM3). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3.

PM3

Detected in trans with pathogenic variant c.1066-11G>A. Parents were also investigated to confirm their carrier status.

PM2

extremely low frequency in gnomAD. MAF=0.00001

PP4_Moderate

Detected in a patient with moderate PKU (Phe levels 9.5 mg/dL), Bh4 deficiency ruled out with urinary pterin analysis, and determination of DHPR activity. PMID: 31355225

PubMed:31355225

PP3

Computational evidence is conflicting: deleterious in SIFT, MutationTaster; benign in PolyPhen2, REVEL=0.711.

PM5

The current variant is the only variant found in this codon in ClinVar.

Approved on: 2020-06-26

Published on: 2020-06-26

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