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_000277.2(PAH):c.969+6T>A

CA229880

102916 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: fed7f4d2-1407-4dcb-b833-9194c1949c66
Approved on: 2020-01-26
Published on: 2020-01-31

HGVS expressions

NM_000277.2:c.969+6T>A
NM_000277.2(PAH):c.969+6T>A
NC_000012.12:g.102846889A>T
CM000674.2:g.102846889A>T
NC_000012.11:g.103240667A>T
CM000674.1:g.103240667A>T
NC_000012.10:g.101764797A>T
NG_008690.1:g.75714T>A
NG_008690.2:g.116522T>A
NM_000277.1:c.969+6T>A
NM_001354304.1:c.969+6T>A
NM_000277.3:c.969+6T>A
ENST00000307000.7:c.954+6T>A
ENST00000549247.6:n.728+6T>A
ENST00000551114.2:n.631+6T>A
ENST00000553106.5:c.969+6T>A
ENST00000635477.1:n.74-2458T>A
ENST00000635528.1:n.484+6T>A
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Uncertain Significance

Met criteria codes 3
PP3 PM3 PP4_Moderate
Not Met criteria codes 1
PM2

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The c.969+6T>A variant in PAH has been reported in 2 patients with benign HPA (BH4 deficiency excluded) (PP4_Moderate; PMID: 8659548, 24941924). It was detected with known pathogenic variant c.1162G>A, (p.Val388Met) (PMID: 24941924). This variant has a frequency of 0.00033 in Latino population, which is higher than our PM2 cut-off (0.0002). A deleterious effect is predicted in HSF and TraP. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3, PP3.
Met criteria codes
PP3
Human splicing finder supports a deleterious effect: “Broken WT donor site: most probably affects splicing”. Fruitfly analysis supports deleterious effect: (.98 reduces to .93 for donor site). TRAP= 0.934.
PM3
Detected with known pathogenic variant c.1162G>A, (p.Val388Met) PMID: 24941924

PP4_Moderate
Reported in 2 patients with benign HPA (240 uM/L, <300 uM on a normal diet). BH4 deficiency excluded. PMID: 8659548, PMID: 24941924

Not Met criteria codes
PM2
Highest MAF=0.00033 in Latino population. Above 0.0002 PAH cut-off. Overall MAF=0.00004.
Curation History
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