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]

Link to SEPIO compliant JSON-LD document

Variant: NM_001354304.2:c.1023G>C

CA386493436

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: defe237b-a3d1-4131-beb4-8625d476067b

HGVS expressions

NM_001354304.2:c.1023G>C

NC_000012.12:g.102844378C>G

CM000674.2:g.102844378C>G

NC_000012.11:g.103238156C>G

CM000674.1:g.103238156C>G

NC_000012.10:g.101762286C>G

NG_008690.1:g.78225G>C

NG_008690.2:g.119033G>C

ENST00000553106.6:c.1023G>C

ENST00000307000.7:c.1008G>C

ENST00000549247.6:n.782G>C

ENST00000551114.2:n.685G>C

ENST00000553106.5:c.1023G>C

ENST00000635477.1:n.127G>C

ENST00000635528.1:n.538G>C

NM_000277.1:c.1023G>C

NM_000277.2:c.1023G>C

NM_001354304.1:c.1023G>C

NM_000277.3:c.1023G>C

Likely Pathogenic

PP4 PP3 PM3 PM2

PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.1023 G>C (p.Lys341Asn) variant in PAH was seen in a patient with mPKU in trans with the pathogenic variant p.Ala434Asp (PMID: 28982351). This variant was found at a very low frequency in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PM2, PP3, PP4.

PP4

Variant was detected in a patient affected with mPKU. Variable sites in patient genes were aligned with the corresponding sites from the respective parents. This was seen in trans with a pathogenic variant listed in ClinVar. Those with BH4 cofactor deficiency were excluded PMID: 28982351

PP3

Predicted to be damaging (SIFT), probably damaging (PolyPhen2), Disease causing (MutationTaster). REVEL=0.874

PM3

This variant was detected in trans with the pathogenic variant p.Ala434Asp (PMID: 28982351). points=1.

PM2

Present in European (Finnish) populations at a frequency of 0.0003981 and in European (non-Finnish) populations at a frequency of 0.00001550 (Gnomad). This variant is absent from the population database Exac.

PM5

Two other variants of unknown significance (p.K341T) and (p.K341R) have been documented in the VCI at this amino acid residue.

Approved on: 2022-07-30

Published on: 2022-07-30

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