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_000277.2(PAH):c.505C>T (p.Arg169Cys)

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CA267693

125436 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1010c67c-c106-47a5-840d-1ea31f14b69a

Approved on: 2019-08-11

Published on: 2019-08-11

HGVS expressions

NM_000277.2:c.505C>T

NM_000277.2(PAH):c.505C>T (p.Arg169Cys)

NC_000012.12:g.102866600G>A

CM000674.2:g.102866600G>A

NC_000012.11:g.103260378G>A

CM000674.1:g.103260378G>A

NC_000012.10:g.101784508G>A

NG_008690.1:g.56003C>T

NG_008690.2:g.96811C>T

NM_000277.1:c.505C>T

NM_001354304.1:c.505C>T

NM_000277.3:c.505C>T

ENST00000307000.7:c.490C>T

ENST00000549111.5:n.601C>T

ENST00000551988.5:n.530+10862C>T

ENST00000553106.5:c.505C>T

Likely Pathogenic

PM3_Strong PP4_Moderate PM2

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.505C>T (p.Arg169Cys) PAH variant has been identified in at least 3 compound heterozygous probands with mild HPA to classic PKU, with at least 1 proband excluding BH4 deficiency (PMIDs: 28771436, 30050108, 30747360). It has been detected in trans with pathogenic variants Arg243Gln (ClinVar 591), Arg408Gln (ClinVar 577), and c.208_210del (ClinVar 102632). This variant occurs and a very low frequency of 0.00001194 in gnomAD. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PP4_Moderate.

PM3_Strong

Arg169Cys has been reported in trans with pathogenic variants Arg243Gln (ClinVar 591), Arg408Gln (ClinVar 577), and c.208_210del (ClinVar 102632). Parents were tested to confirm carrier status.

Patient NBS51 was identified as compound heterozygous for c.505C>T and c.208_210del (ClinVar 102632, Pathogenic). PubMed:28771436

Two compound heterozygotes were reported. One patient with Arg169Cys and Arg243Gln (ClinVar 591, Pathogenic) and another with Arg169Cys and Arg408Gln (ClinVar 577, Pathogenic). Parents were tested to confirm carrier status. PubMed:30050108

PP4_Moderate

At least three compound heterozygous patients with Arg169Cys have been reported with mild hyperphenylalaninemia (Phe 120-600 umol/L). A defect in BH4 cofactor metabolism was excluded in at least one case.

Two compound heterozygous patients with Arg169Cys had mild hyperphenylalaninemia (Phe 120-600 umol/L). PubMed:30050108

One Arg169Cys allele was identified in a MHP case (Phe: 120 ~ 360 μmol/L) with tetrahydrobiopterin deficiency excluded through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay on DBS samples. PubMed:30747360

PM2

The overall allele frequency in gnomAD is 0.00001194 with and MAF of 0.00003266 (1/30616) in the South Asian population (below the <0.0002 threshold).

PP3

Computational evidence does not reach consensus to support a deleterious effect (REVEL score of 0.678).

Curation History

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