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]

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Variant: NM_000277.2(PAH):c.969+6T>A

CA229880

102916 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: fed7f4d2-1407-4dcb-b833-9194c1949c66

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

Uncertain Significance

PP3 PP4_Moderate PM3

PM2

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

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.

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.

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

Likely same patient as Guldberg, et al. Benign persistent hyperphenylalaninemia was diagnosed in cases with the untreated PHE level of 4-9.9 mg/dl (200-600 μM), normal level of Biopterin and the tyrosine level < 3 mg/dl. PubMed:11385716

c.969+6T>A detected in 1 patient with benign HPA. Patients with transient HPA or with HPA due to a defect in the synthesis or recycling of the cofactor BH4 were excluded. PubMed:24941924

"IVS9nt6t>a" detected on 1 allele (Patient A/4097/AZA-10, Phe level 240, MHP, English/Mexican) PubMed:8659548

PM3

Detected with known pathogenic variant c.1162G>A, (p.Val388Met) PMID: 24941924

detected with c.1162G>A, p.(Val388Met) (VarID619, pathogenic) PubMed:24941924

PM2

Highest MAF=0.00033 in Latino population. Above 0.0002 PAH cut-off. Overall MAF=0.00004.

Approved on: 2020-01-26

Published on: 2020-01-31

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