Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

Variant: NM_000277.3(PAH):c.442G>A (p.Gly148Ser)

CA229551

102680 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: b741dc6c-848d-40ed-83d7-1446a4bfbaa1
Approved on: 2019-12-22
Published on: 2019-12-22

HGVS expressions

NM_000277.3:c.442G>A
NM_000277.3(PAH):c.442G>A (p.Gly148Ser)
NC_000012.12:g.102866663C>T
CM000674.2:g.102866663C>T
NC_000012.11:g.103260441C>T
CM000674.1:g.103260441C>T
NC_000012.10:g.101784571C>T
NG_008690.1:g.55940G>A
NG_008690.2:g.96748G>A
NM_000277.1:c.442G>A
NM_000277.2:c.442G>A
NM_001354304.1:c.442G>A
ENST00000307000.7:c.427G>A
ENST00000549111.5:n.538G>A
ENST00000551988.5:n.530+10799G>A
ENST00000553106.5:c.442G>A
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Likely Pathogenic

Met criteria codes 4
PP3 PP4 PM2 PM3

Evidence Links 4

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The PAH variant c.442G>A (p.Gly148Ser) has been reported in three individuals with PHA deficiency (Phe levels >120 μM). One patient from the Northeastern region of the US, (PMID: 8659548)(PMID:10429004), one patient from Europe (PMID: 10679941), and one patient from the Campania Region in Southern Italy with mild PKU (Phe between 600 and 1200 μM) (PMID: 17096675). The variant c.442G>A (p.Gly148Ser) was document with the pathogenic variant c.194T>C (p.Ile65Thr)(ClinVar ID: 636), and with the pathogenic variant c.473G>A (p.Arg158Gln)(ClinVar ID: 587) (PMID: 8535445). According to gnomAD, this variant is present at a low allele frequency in population databases, with the highest reported frequency in the African population (0.00006). In silico modeling predicts that this missense variant is damaging by SIFT, probably damaging by Polyphen 2 and disease causing by Mutation Taster. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, and PP4 .
Met criteria codes
PP3
Predicted to be damaged by SIFT, probably damaging by Polyphen 2 and disease-causing by Mutation Taster.
PP4
The PAH variant c.442G>A (p.Gly148Ser) has been reported in three individuals with PHA deficiency (Phe levels >120 μM). One patient from the Northeastern region of the US, (PMID: 8659548)(PMID:10429004), one patient from Europe (PMID: 10679941), and one patient from the Campania Region in Southern Italy with mild PKU (Phe between 600 and 1200 μM) (PMID: 17096675).
PubMed:10679941
PubMed:17096675
PubMed:8659548
PM2
According to gnomAD, this variant is present at a low allele frequency in population databases, with the highest reported frequency in the African population (0.00006).
PM3
The variant c.442G>A (p.Gly148Ser) was document with the pathogenic variant c.194T>C (p.Ile65Thr)(ClinVar ID: 636) in a family with a phenotype of moderate + normal retardation, and with the pathogenic variant c.473G>A (p.Arg158Gln)(ClinVar ID: 587) in a family with a moderate retardation phenotype. The families belong to a study of 4 families with untreated PKU in Australia.(PMID: 8535445).
PubMed:8535445
Curation History
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