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.208T>C (p.Ser70Pro)

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Curation History
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CA229488

102631 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 12dc078f-4f90-4e29-a304-abfd5153cb71

Approved on: 2022-03-11

Published on: 2022-04-16

HGVS expressions

NM_000277.3:c.208T>C

NM_000277.3(PAH):c.208T>C (p.Ser70Pro)

NC_000012.12:g.102894879A>G

CM000674.2:g.102894879A>G

NC_000012.11:g.103288657A>G

CM000674.1:g.103288657A>G

NC_000012.10:g.101812787A>G

NG_008690.1:g.27724T>C

NG_008690.2:g.68532T>C

ENST00000553106.6:c.208T>C

ENST00000307000.7:c.193T>C

ENST00000546844.1:c.208T>C

ENST00000548677.2:n.295T>C

ENST00000548928.1:n.130T>C

ENST00000549111.5:n.304T>C

ENST00000550978.6:n.192T>C

ENST00000551337.5:c.208T>C

ENST00000551988.5:n.297T>C

ENST00000553106.5:c.208T>C

ENST00000635500.1:n.176T>C

NM_000277.1:c.208T>C

NM_000277.2:c.208T>C

NM_001354304.1:c.208T>C

NM_001354304.2:c.208T>C

Likely Pathogenic

PP4_Moderate PM2 PP3 PM3_Supporting PS3_Supporting

PM5 PP1

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.208T>C (p.Ser70Pro) variant in PAH has been reported in at least four individuals with hyperphenylalanemia, including at least one for whom BH4 deficiency was excluded (PMID: 9860305, PMID: 21307867). Of these, two were siblings who also had p.Arg241His (PMID: 22330942), which is classified as pathogenic by PAH VCEP (Variation ID: 102804), without documentation of parental testing to establish phase. In-vitro studies show 20% enzyme activity (PMID: 9860305). This variant is absent from 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: PP3, PP4, PM2, PM3_Supporting, PS3_supporting.

PP4_Moderate

p.Ser70Pro observed in association with PAH deficiency with BH4 deficiency excluded, but without documented plasma phenylalanine levels (PMID: 9860305, PMID: 21307867). Plasma Phe levels >120 umol/L without documentation of exclusion of BH4 deficiency (PMID: 22330942).

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, or ESP

PP3

Damaging in SIFT, probably damaging in PP-2, disease-causing in MutationTaster, REVEL=0.968

PM3_Supporting

Two sibs with p.Ser70Pro and p.Arg241His (classified as Path by PAH VCEP, Variation ID: 102804). However, phase undescribed. Per SVI guidelines "If the phase cannot be determined, it is recommended that at least two different LP/P variants (depending on classifications) are needed to equal the weight of one LP/P co-occurrence confirmed in trans." Only one LP/P variant in this case, as these are two related individuals, so this situation reflects 0.5 points for one (phase unknown) occurrence of Ser70Pro with Arg241His.

PS3_Supporting

Okano et al. 1998 PMID: 9860305 – in vitro PAH activity of mutant PAH cDNA construct in a COS cell expression system showed mean enzyme activity 20% of wild-type. PS3_supp approved for use for this PMID on PAH VCEP call 2/25/22.

PM5

c.209C>T(p.Ser70Phe) classified as likely pathogenic by PAH VCEP (Variation ID: 987767). PM5 not met as p.Ser70Phe is likely path and not path.

PP1

Two affected segregations and no unaffected segregations noted. However, parental testing for phase not discussed (PMID: 22330942).

Curation History

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