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.329C>T (p.Ser110Leu)

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Curation History
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CA229516

102651 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: fa22eff0-ef3f-4eef-a040-0550adb5ba5f

Approved on: 2021-12-16

Published on: 2022-04-16

HGVS expressions

NM_000277.3:c.329C>T

NM_000277.3(PAH):c.329C>T (p.Ser110Leu)

NC_000012.12:g.102894758G>A

CM000674.2:g.102894758G>A

NC_000012.11:g.103288536G>A

CM000674.1:g.103288536G>A

NC_000012.10:g.101812666G>A

NG_008690.1:g.27845C>T

NG_008690.2:g.68653C>T

ENST00000553106.6:c.329C>T

ENST00000307000.7:c.314C>T

ENST00000546844.1:c.329C>T

ENST00000548928.1:n.251C>T

ENST00000549111.5:n.425C>T

ENST00000550978.6:n.313C>T

ENST00000551337.5:c.329C>T

ENST00000551988.5:n.418C>T

ENST00000553106.5:c.329C>T

NM_000277.1:c.329C>T

NM_000277.2:c.329C>T

NM_001354304.1:c.329C>T

NM_001354304.2:c.329C>T

Likely Pathogenic

PP4_Moderate PM2 PM3

PP3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.329C>T (p.Ser110Leu) variant in PAH has been reported in one individual with mild hyperphenylalanemia, in trans to c.842C>T (p.Pro281Leu) (Likely pathogenic by PAH VCEP variation ID: 589) with exclusion of BH4 deficiency (PMID: 16051511, PMID: 12618080). It has also been observed in an additional patient with hyperphenylalanemia without specified exclusion of BH4 deficiency (PMID: 26542770). In-vitro functional studies are unavailable. This variant is absent from population databases. In-silico predictions yield conflicting results regarding the pathogenicity of this variant. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PP4_moderate, PM2.

PP4_Moderate

Observed in a patient with mild hyperphenylalanemia with plasma phe levels exceeding 240umol/L. "A defect of BH4 synthesis or regeneration was excluded by measuring dihydropteridine reductase activity in dried blood filter card samples and by determination of pterins in urine samples collected before and during BH4 loading tests." (PMID: 16051511). Also observed in a second patient with hypherphenylalanemia with Phe level 293 umol/L. Exclusion of BH4 deficiency not specified (PMID: 26542770).

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, and ESP.

PM3

Observed with c.842C>T (p.Pro281Leu) (Likely pathogenic by PAH VCEP variation ID: 589), confirmed in trans (PMID: 16051511).

PP3

Tolerated and Damaging in SIFT, Probably Damaging in PP-2, Disease-causing in MutationTaster, REVEL=0.717

Curation History

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