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.1200-8G>A

CA229395

102565 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: efeae3bc-42d1-44aa-9a8b-de32b8bad069

Approved on: 2019-09-29

Published on: 2019-09-29

HGVS expressions

NM_000277.2:c.1200-8G>A

NM_000277.2(PAH):c.1200-8G>A

NC_000012.12:g.102840523C>T

CM000674.2:g.102840523C>T

NC_000012.11:g.103234301C>T

CM000674.1:g.103234301C>T

NC_000012.10:g.101758431C>T

NG_008690.1:g.82080G>A

NG_008690.2:g.122888G>A

NM_000277.1:c.1200-8G>A

NM_001354304.1:c.1200-8G>A

NM_000277.3:c.1200-8G>A

ENST00000307000.7:c.1185-8G>A

ENST00000549247.6:n.959-8G>A

ENST00000551114.2:n.862-8G>A

ENST00000553106.5:c.1200-8G>A

ENST00000635477.1:n.304-8G>A

ENST00000635528.1:n.715-8G>A

Likely Pathogenic

PM2 PM3 PP4_Moderate PP3

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1200-8G>A variant in PAH has been reported in multiple patients with PAH deficiency. BH4 deficiency excluded (PMID: 9391881, 23062575). This variant has extremely low frequency in gnomAD (MAF=0.00001) (PM2). This variant was detected with known pathogenic variants IVS10-11G>A, p.A403V (PM3). Computational evidence supports a splicing effect (HSF and MaxEnt). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3.

PM2

Extremely low frequency in gnomAD (MAF=0.00001)

PM3

Detected with known pathogenic variants IVS10-11G>A, p.A403V. Parental confirmation not reported.

Patients 7.1 and 7.2 genotype: IVS11-8G>A/IVS10-11G>A. Parental confirmation not reported. PubMed:12409276

Patient 2 genotype: IVS11-8G>A/p.A403V. Parental analysis not reported. PubMed:23062575

PP4_Moderate

Detected in multiple patients with PAH deficiency. BH4 deficiency excluded (PMID: 9391881, 23062575)

Detected in Patient 2: IVS11-8G>A, BH4 deficiency excluded. PubMed:23062575

Transition of G to A in the 3'splice site of intron 11 at position-8 (IVS11nt-8g>a) detected on 4 alleles. PubMed:9391881

PP3

HSF: Activation of an intronic cryptic acceptor site (+61.02%). Potential alteration of splicing. MaxEnt: Alteration of the WT acceptor site, most probably affecting splicing (-70.4%).

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