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_000277.1(PAH):c.967_969delACA (p.Thr323del)

CA229876

102913 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 415850ec-8284-4760-a5cc-4383c207b56f

HGVS expressions

NM_000277.1:c.967_969delACA

NM_000277.1(PAH):c.967_969delACA (p.Thr323del)

NC_000012.12:g.102846895_102846897del

CM000674.2:g.102846895_102846897del

NC_000012.11:g.103240673_103240675del

CM000674.1:g.103240673_103240675del

NC_000012.10:g.101764803_101764805del

NG_008690.1:g.75706_75708del

NG_008690.2:g.116514_116516del

NM_000277.1:c.967_969del

NM_000277.2:c.967_969del

NM_001354304.1:c.967_969del

NM_000277.3:c.967_969del

ENST00000307000.7:c.952_954del

ENST00000549247.6:n.726_728del

ENST00000551114.2:n.629_631del

ENST00000553106.5:c.967_969del

ENST00000635477.1:n.74-2466_74-2464del

ENST00000635528.1:n.482_484del

Pathogenic

PP4_Moderate PM3_Strong PM4 PM2

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in gnomAD: 0.000008131; PM4: Protein length change as a results of in-frame deletion; PP4_Moderate: T323del found in 2 PKU patients. BH4 deficiency excluded. Upgraded per ClinGen Metabolic workgroup. (PMID:21147011); PM3_Strong: T323del detected with P281 in 1 PKU patient, and L48S in another PKU patient. Both pathogenic. Upgraded per ClinGen SVI Workgroup. (PMID:21147011). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM4, PP4_Moderate, PM3_Strong).

PP4_Moderate

T323del found in 2 PKU patients. BH4 deficiency excluded. Upgraded per ClinGen Metabolic workgroup.

588 hyperphenylalaninemic patients were investigated. Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). T323del found on 2 alleles in 2 patients. PubMed:21147011

PM3_Strong

T323del detected with P281 in 1 PKU patient, and L48S in another PKU patient. Both pathogenic. Upgraded per ClinGen SVI Workgroup.

T323del seen in 2 PKU patients. Once with P281L (VarID589, Pathogenic); once with L48S (VarID608, Pathogenic). PubMed:21147011

PM4

Protein length change as a results of in-frame deletion

PM2

Extremely low frequency in gnomAD: 0.000008131

Approved on: 2018-08-10

Published on: 2019-04-05

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