Evidence Repository - Clinical Genome Resources

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Variant: NM_000277.1:c.1256A>G

CA6748705

552488 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 862ed3b1-5ae5-4a75-b54a-a63610bf638b

Approved on: 2020-06-22

Published on: 2021-09-19

HGVS expressions

NM_000277.1:c.1256A>G

ENST00000553106.6:c.1256A>G

ENST00000307000.7:c.1241A>G

ENST00000551114.2:n.918A>G

ENST00000553106.5:c.1256A>G

ENST00000635477.1:n.360A>G

ENST00000635528.1:n.771A>G

NM_000277.2:c.1256A>G

NM_001354304.1:c.1256A>G

NM_000277.3:c.1256A>G

NM_001354304.2:c.1256A>G

NC_000012.12:g.102840459T>C

CM000674.2:g.102840459T>C

NC_000012.11:g.103234237T>C

CM000674.1:g.103234237T>C

NC_000012.10:g.101758367T>C

NG_008690.1:g.82144A>G

NG_008690.2:g.122952A>G

Pathogenic

PM3_Very Strong PM2 PP4_Moderate

PP3 PM5 PS3

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1256A>G (p.Gln419Arg) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 17096675, PMID: 26503515). This variant has an extremely low allele frequency (MAF=0.00016) in gnomAD. This variant was detected in trans with multiple pathogenic variants: p.S231P (PMID: 18346471); p.Ala434Asp (PMID: 25456745); c.1068C>A (p.Y356*) (PMID: 26322415); p.Arg413Pro; p.Ala403Val; p.Val399=; p.Arg243Gln (2 patients); p.Arg53His (US); EX6-96A＞G (PMID: 28982351). Computational prediction tools are conflicting. PAH-specific ACMG/AMP criteria applied: PM3_ very-strong, PM2, PP4_Moderate.

PM3_Very Strong

Detected with p.S231P (P 3 submitters), parental analysis not reported PMID: 18346471 p.Ala434Asp (LP) parental analysis not reported PMID: 25456745; 1068C>A (p.Y356*) (P 6 submitters) All mutations identified in patients were confirmed by analyzing parental DNA. PMID: 26322415 p.Arg413Pro (P 6 submitters); p.Ala403Val (P 17 submitters); p.Val399= (P 5 submitters); p.Arg243Gln (2 patients, P 11 submitters); p.Arg53His (US); EX6-96A＞G (P 6 submitters). variable sites in patient genes were aligned with the corresponding sites from the respective parents. PMID: 28982351 8.0 pts

PM2

Absent from 1000 genomes, and low freq in gnomAD (MAF=0.00016)

PP4_Moderate

Seen in multiple individuals (18) with PKU. These patients were diagnosed at birth either through a neonatal screening program or based on clinical presentation. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. PMID: 17096675, PMID: 26503515

These patients were diagnosed at birth either through a neonatal screening program or based on clinical presentation. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. PubMed:26503515

Seen in an individual with mild PKU with a 'severe' second allele PubMed:17096675

PP3

Conflicting evidence. Predicted tolerated by SIFT, possibly damaging from Polyphen and disease causing by MutationTaster.

PM5

p.Q419P not found in ClinVar.

PS3

the residual enzyme activity in cells expressing mutant cDNA was 71% (p.Q419R) that of the wild-type enzyme activity. PMID: 18346471 The residual activities of the mutant PAH enzymes, expressed as a percentage of wild-type enzyme activity, were 63±5% (p.Q419R). The profiles of the wild-type PAH and of mutant p.Q419R in which dimer is the dominant species (instead of wt tetramer). PMID: 21820508

we expressed five proteins, each containing one of the five novel mutations (p.N223Y, p.R297L, p.F382L, p.K398N, p.Q419R) previously identified by our group, to investigate the in vitro PAH activity of the mutant enzymes. All transfections were performed in triplicate. Each triplicate was assayed for total protein content using a protein assay kit. Parental vector pcDNA3, without insert, was transfected as negative control.We co-transfected 10 μg of a construct carrying a β-galactosidase reporter gene as a control for transfection efficiency. For each transfection, PAH activity was assayed on 50 µg of proteins, in duplicate. Enzyme activity of the wild-type and mutant PAH constructs was measured; the mean PAH activities were calculated from the three sets of transfection data. The residual activities of mutant PAH enzymes were expressed as a percentage of wild-type enzyme activity and normalized to transfection efficiencies based on replicate β-galactosidase activities. the residual enzyme activity in cells expressing mutant cDNAs was 70% (p.N223Y), 42% (p.R297L), 56% (p.F382L), 55% (p.K398N) and 71% (p.Q419R) that of the wild-type enzyme activity. There was no enzyme activity in the untransduced cells. PubMed:18346471

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