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_000277.1(PAH):c.898G>T (p.Ala300Ser)

CA273108

92751 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: 1cd06d79-1c2c-4338-936e-15faf0063222
Approved on: 2018-08-10
Published on: 2019-04-05

HGVS expressions

NM_000277.1:c.898G>T
NM_000277.1(PAH):c.898G>T (p.Ala300Ser)
NC_000012.12:g.102851701C>A
CM000674.2:g.102851701C>A
NC_000012.11:g.103245479C>A
CM000674.1:g.103245479C>A
NC_000012.10:g.101769609C>A
NG_008690.1:g.70902G>T
NG_008690.2:g.111710G>T
NM_000277.2:c.898G>T
NM_001354304.1:c.898G>T
NM_000277.3:c.898G>T
ENST00000307000.7:c.883G>T
ENST00000549247.6:n.657G>T
ENST00000551114.2:n.560G>T
ENST00000553106.5:c.898G>T
ENST00000635477.1:n.59G>T

Pathogenic

Met criteria codes 4
PS3 PP3 PP4_Moderate PM3_Very Strong
Not Met criteria codes 2
PM5 PM2

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
PAH-specific ACMG/AMP criteria applied: PP3: Deleterious in SIFT, Polyphen2, MutationTaster; PP4_Moderate: A300S found on 56/588 hyperphenylalaninemic patients, BH4 deficiency excluded. Upgraded per ClinGen Metabolic WG. (PMID:21147011); PM3_VeryStrong: Detected with c.1066-11G>A (P), R261Q(P/LP), L48S (P), R176X (P) in 20 patients. (PMID:21147011); PS3: A300S in vitro PAH activity of 31% (PMID:17935162). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PP4_Moderate, PM3_VeryStrong, PS3).
Met criteria codes
PS3
A300S in vitro PAH activity of 31%

PP3
Deleterious in SIFT, Polyphen2, MutationTaster
PP4_Moderate
A300S found on 56/588 hyperphenylalaninemic patients, BH4 deficiency excluded. Upgraded per ClinGen Metabolic WG.

PM3_Very Strong
Detected with c.1066-11G>A (P), R261Q(P/LP), L48S (P), R176X (P) in 20 patients.

Not Met criteria codes
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
MAF in gnomAD: 0.00661
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