The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000277.3(PAH):c.1175T>C (p.Phe392Ser)

CA229369

102544 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: 4a89f184-bab9-45d5-b0eb-0ad48c77ec55
Approved on: 2024-11-17
Published on: 2024-11-18

HGVS expressions

NM_000277.3:c.1175T>C
NM_000277.3(PAH):c.1175T>C (p.Phe392Ser)
NC_000012.12:g.102843670A>G
CM000674.2:g.102843670A>G
NC_000012.11:g.103237448A>G
CM000674.1:g.103237448A>G
NC_000012.10:g.101761578A>G
NG_008690.1:g.78933T>C
NG_008690.2:g.119741T>C
ENST00000553106.6:c.1175T>C
ENST00000307000.7:c.1160T>C
ENST00000549247.6:n.934T>C
ENST00000551114.2:n.837T>C
ENST00000553106.5:c.1175T>C
ENST00000635477.1:c.279T>C
ENST00000635528.1:n.690T>C
NM_000277.1:c.1175T>C
NM_000277.2:c.1175T>C
NM_001354304.1:c.1175T>C
NM_001354304.2:c.1175T>C
More

Likely Pathogenic

Met criteria codes 3
PP3_Strong PM2_Supporting PM5
Not Met criteria codes 1
PP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The c.1175T>C (p.Phe392Ser) variant in PAH was reported in one individual with PAH deficiency; however, this report was non-English article that is not accessible and thus cannot be used as case-level evidence at this time (PMID: 22333022). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and is predicted damaging by REVEL = 0.98 (PP3_Strong). A different missense variant at the same position, p.F392I, is reported as pathogenic in ClinVar (VarID: 853581) (PM5). In summary, this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: PM2_Supporting, PM5, PP3_Strong.
Met criteria codes
PP3_Strong
REVEL score 0.98.
PM2_Supporting
Variant absent from gnomAD v4.1.0
PM5
A different missense variant at the same position, p.F392I, is reported as pathogenic in ClinVar by PAH VCEP (VarID:853581)
Not Met criteria codes
PP4
F392S reported in one patient with PAH deficiency (PMID: 22333022). Not able to access full description of methods due to article being in Chinese.
Curation History
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