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_000277.1(PAH):c.1066-11G>A

CA251538

607 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 2470a255-3083-4956-9ff7-176203d54920

HGVS expressions

NM_000277.1:c.1066-11G>A

NM_000277.1(PAH):c.1066-11G>A

NC_000012.12:g.102843790C>T

CM000674.2:g.102843790C>T

NC_000012.11:g.103237568C>T

CM000674.1:g.103237568C>T

NC_000012.10:g.101761698C>T

NG_008690.1:g.78813G>A

NG_008690.2:g.119621G>A

NM_000277.2:c.1066-11G>A

NM_001354304.1:c.1066-11G>A

NM_000277.3:c.1066-11G>A

ENST00000307000.7:c.1051-11G>A

ENST00000549247.6:n.825-11G>A

ENST00000551114.2:n.728-11G>A

ENST00000553106.5:c.1066-11G>A

ENST00000635477.1:n.170-11G>A

ENST00000635528.1:n.581-11G>A

Pathogenic

PS3 PP4_Moderate PP3 PM3_Strong

PM5 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.1066-11G>A variant in PAH has been reported in > 76 PKU alleles (BH4 deficiency excluded). (PP4_Moderate; PMID: 23500595; PMID: 8990013). This variant has 0% enzyme activity (PS3; http://www.biopku.org/centralStore/biopku/PAH%20activity.pdf). This variant was detected in trans with multiple known pathogenic variants: p.R243Q, p.R243X, p.R261Q, p.R270K, p.I65T. (PM3_Strong; PMID: 23500595; PMID: 8990013). Computational prediction tools and conservation analysis suggest that the c.1066-11G>A variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Strong

PS3

In vitro functional studies support a damaging effect on the gene (alternative splicing) and gene product (no PAH activity)

Direct sequence analysis of exon 11 and flanking introns in a comp. het PKU patient revealed a G>A in intron 10 (nt 546), located 11 bp upstream from the intron 10/exon 11 boundary. No other PKU mutation was found on this allele. PCR-amplified intron 10 sequences (homozygous normal and mutant) were inserted into PAH cDNA cloned into pSVL and transfected into monkey COS cells. Isolated RNA was used for cDNA synthesis, which was then sequenced. Control had the correct sequence. Mutant had a slightly longer fragment and 9 additional nt. Inserted between exon 10 and 11, proving creation of a splice acceptor site in the mutant. Also, presence of the mutant protein in the PKU patient’s liver was shown by Western blot. PAH activity assay showed no conversion of C-14 labeled Phe into Tyr. PubMed:1769645

PP4_Moderate

IVS10-11G>A seen in > 76 PKU alleles. BH4 deficiency ruled out in 1 study with 29 alleles. Upgraded per ClinGen Metabolic workgroup

150 HPA patients were diagnosed, 123 were detected by NBS and 27 by clinical symptoms or family study. All the patients studied with transient HPA were excluded. None of the patients with HPA was caused by defects in the synthesis or recycling of the cofactor BH4. IVS10-11G>A was seen on 29 alleles. PubMed:23500595

A total of 11 Gypsy PKU patients were screened for the presence of IVS10nt546. Among them, 8 were found to be homozygous for this mutation and 3 heterozygous. A total of 23 non-Gypsy unrelated PKU patients from different regions of Spain were also included. All carry mutation IVS10nt546: 8 in homozygous fashion and 15 in heterozygous fashion. All had Phe at diagnosis of >13 mg/dl. PubMed:8990013

PP3

Predicted in affect splicing in HSF and MaxEnt. Conserved in 25/31 vertebrates.

PM3_Strong

Detected with: p.R243Q (P); p.R243X (P); p.R261Q (P/LP); p.R270K (P); p.I65T (P/LP). PMID: 23500595; PMID: 8990013.

IVS10-11G>A was seen on 29 alleles. Patient 3: p.R243Q/IVS10-11G>A (VarID591, Pathogenic). Patient 4: p.R243X/IVS10-11G>A. (VarID588, Pathogenic). Patient 6: p.R261Q/IVS10-11G>A (VarID582, P/LP). Patient 8: p.R270K/IVS10-11G>A (VarID102846, Pathogenic). Patient 10: p.I65T/IVS10-11G>A (VarID636, P/LP). PubMed:23500595

11 Gypsy PKU patients were screened for the presence of IVS10nt546. 8 were homozygous and 3 heterozygous. R252W was found in two heterozygous siblings. (VarID 584, P/LP). The results were confirmed in the parents. 23 non-Gypsy unrelated PKU patientsl carry mutation IVS10nt546: 8 homozygotes and 15 compound heterozygous. PubMed:8990013

PM5

Current variant is in non-coding region

PM2

Does not meet PAH EP PM2 cutoff (<0.0002): MAF in 1000G EUR, AF=0.00298 (3/1006); 0.0002424 in gnomAD

Approved on: 2018-10-01

Published on: 2019-04-05

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