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]

Variant: NM_000277.3(PAH):c.532G>A (p.Glu178Lys)

CA16020812

928885 (ClinVar)

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: c54336ad-7a33-4a07-895c-275c08ab017c

Approved on: 2021-01-17

Published on: 2021-02-12

HGVS expressions

NM_000277.3:c.532G>A

NM_000277.3(PAH):c.532G>A (p.Glu178Lys)

NC_000012.12:g.102855310C>T

CM000674.2:g.102855310C>T

NC_000012.11:g.103249088C>T

CM000674.1:g.103249088C>T

NC_000012.10:g.101773218C>T

NG_008690.1:g.67293G>A

NG_008690.2:g.108101G>A

NM_000277.1:c.532G>A

NM_000277.2:c.532G>A

NM_001354304.1:c.532G>A

NM_001354304.2:c.532G>A

ENST00000307000.7:c.517G>A

ENST00000549111.5:n.628G>A

ENST00000551988.5:n.553G>A

ENST00000553106.5:c.532G>A

Pathogenic

PM3_Strong PP4_Moderate PM2 PM5

PP3 PS3

Evidence Links 5

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.532G>A (p.Glu178Lys) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 26503515; PMID: 26542770). This variant has an extremely low allele frequency (PopMax MAF=0.00006, ENF) in gnomAD (PM2). This variant was detected in trans with F39del (PMID: 26542770) (Pathogenic/Likely Pathogenic in ClinVar by 7 submitters, see ID 188933). It has also been observed with R408W (PMID: 28771436, parental testing not performed) (Pathogenic in ClinVar (ID 577) and by ClinGen PAH VCEP) and IVS4-1G>A (PMID: 29316886, parental testing unclear) (Pathogenic in ClinVar (ID 594) and by ClinGen PAH VCEP). Computational prediction tools and conservation analysis are conflicting. This is a novel missense change at an amino acid residue where a different pathogenic missense change has been seen before (c.533A>G (p.Glu178Gly). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_strong, PM2, PM5

PM3_Strong

detected in trans with F39del (PMID: 26542770, Parental testing confirmed that the two mutations identified in the 368 patients all were present in trans.) and R408W (PMID: 28771436, parental testing not performed) and IVS4-1G>A (PMID: 29316886, variable sites in patient genes were aligned with the corresponding sites from the respective parents.)

detected in trans with F39del. Parental testing confirmed that the two mutations identified in the 368 patients all were present in trans. PubMed:26542770

Sample NBS47: c.1222C>T (R408W,P)/c.532G>A. Parental testing not performed. PubMed:28771436

Patient 496: IVS4-1G＞A/p.Glu178Lys. Peripheral blood samples were collected from the patients and parents in each of the 643 core families. To determine sequence variability, variable sites in patient genes were aligned with the corresponding sites from the respective parents. PubMed:29316886

PP4_Moderate

Detected in Chinese PKU patient, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading were assessed. PMID: 26503515 Detected in a Danish patient with probable MHP. PMID: 26542770

Patient 4, probably MHP (lost to follow-up). All patients had PKU according to biochemical criteria. PubMed:26542770

A total of 796 unrelated patients from 29 separate newborn screening centres of China were enrolled. These patients were diagnosed at birth either through a neonatal screening program or based on clinical presentation. Demographic data, including age, consanguinity, family history, and geographical origin, and biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. One patient had c.532G>A (p.E178K). PubMed:26503515

PM2

MAF=0.00006 in ENF gnomAD population.

PM5

c.533A>G (p.Glu178Gly) Pathogenic by 6 submitters

PP3

SIFT=T, Polyphen2=B, MutationTaster=D. REVEL=0.607

PS3

did not affect the transcription of the PAH gene, however, PAH protein synthesis and/or stability was disturbed. PMID: 29653233

We performed site-directed mutagenesis and in vitro expression (E. coli and HEK293T). The mRNA and protein levels of three variants were compared with that of wild type gene, as well as a common PAH mutation, p.R243Q, which is known to decrease protein expression and enzyme activity (Pey et al., 2003). Table 2: E178K mRNA 0.973 ± 0.181, empty control 0, wt 1.0. The lower expression in mutant groups indicated that PAH protein expression was impaired by variants. In general, all four mutations did not affect the transcription of the PAH gene, however, PAH protein synthesis and/or stability was disturbed. Exact numbers or % of wt were not reported. PubMed:29653233

Curation History

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