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_000277.3(PAH):c.938C>T (p.Ala313Val)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229861

102903 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0a96804f-a9d8-44e3-aa66-b85b0dbe231d

Approved on: 2023-07-23

Published on: 2023-07-23

HGVS expressions

NM_000277.3:c.938C>T

NM_000277.3(PAH):c.938C>T (p.Ala313Val)

NC_000012.12:g.102846926G>A

CM000674.2:g.102846926G>A

NC_000012.11:g.103240704G>A

CM000674.1:g.103240704G>A

NC_000012.10:g.101764834G>A

NG_008690.1:g.75677C>T

NG_008690.2:g.116485C>T

ENST00000553106.6:c.938C>T

ENST00000307000.7:c.923C>T

ENST00000549247.6:n.697C>T

ENST00000551114.2:n.600C>T

ENST00000553106.5:c.938C>T

ENST00000635477.1:n.74-2495C>T

ENST00000635528.1:n.453C>T

NM_000277.1:c.938C>T

NM_000277.2:c.938C>T

NM_001354304.1:c.938C>T

NM_001354304.2:c.938C>T

Pathogenic

PP4_Moderate PM2_Supporting PP3_Moderate PS3_Supporting PM3_Strong

BP4 PM5 BS3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The NM_000277.3:c.938C>T variant in PAH is a missense variant predicted to cause substitution of alanine by valine at amino acid 313 (p.Ala313Val). This variant has been detected in at least 8 unrelated individuals with PAH deficiency (PMID: 32668217, PMID: 27121329, PMID: 33465300, PMID: 10234516, PMID: 23500595). Of these individuals, 6 were compound heterozygotes for the variant and pathogenic variants, p.Ala104Asp, c.1066-11G>A, p.Arg408Trp, p.Ex5del4232ins268, p.Gln267Ter, in unknown phase (PMID: 32668217, PMID: 27121329, PMID: 33465300) (3pts total, PM3_Strong). Of these individuals, two had plasma phenylalanine >120 μmol/L with the exclusion of a defect of BH4 cofactor metabolism (PP4_Moderate) (PMID: 10234516, PMID: 23500595). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In a PAH enzyme assay, this variant showed 32% (<50%) of wild-type PAH enzyme activity (PMID: 18590700) (PS3_Supporting). The computational predictor REVEL gives a score of 0.907 which is above the threshold of 0.75, evidence that correlates with impact to PAH function (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 102903, 1 star review status) with one submitter classifying the variant as pathogenic and one submitter classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): PS3_Supporting, PM2_Supporting, PM3_Strong, PP3_Moderate, PP4.

PP4_Moderate

Of these individuals, two had plasma phenylalanine >120 μmol/L with the exclusion of a defect of BH4 cofactor metabolism (PP4_Moderate) (PMID: 10234516, PMID: 23500595).

PM2_Supporting

This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

PP3_Moderate

The computational predictor REVEL gives a score of 0.907 which is above the threshold of 0.75, evidence that correlates with impact to PAH function (PP3_Moderate).

PS3_Supporting

PMID: 18590700: in COS-1 cell system, variant showed 32% (<50%) of wild-type PAH enzyme activity

PM3_Strong

This variant has been detected in at least 8 unrelated individuals with PAH deficiency (PMID: 32668217, PMID: 27121329, PMID: 33465300, PMID: 10234516, PMID: 23500595). Of these individuals, 6 were compound heterozygotes for the variant and pathogenic variants, p.Ala104Asp, c.1066-11G>A, p.Arg408Trp, p.Ex5del4232ins268, p.Gln267Ter, in unknown phase (PMID: 32668217, PMID: 27121329, PMID: 33465300) (3pts total, PM3_Strong).

BP4

All predictors suggest damaging effect. REVEL =0.907

PM5

Both path/likely path and VUS reported at same amino acid residue: c.937G>A (p.Ala313Thr) is VUS in ClinVar; c.938C>A (p.Ala313Glu) is likely path (1 submitter); c.937G>C (p.Ala313Pro) is path (1 submitter)

BS3

Mutation ID#11 with residual enzyme activity 32%

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.