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.60G>C (p.Gln20His)

CA229651

102757 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b36724d2-acba-40d1-a81f-071cd7340281

HGVS expressions

NM_000277.2:c.60G>C

NM_000277.2(PAH):c.60G>C (p.Gln20His)

NC_000012.12:g.102917071C>G

CM000674.2:g.102917071C>G

NC_000012.11:g.103310849C>G

CM000674.1:g.103310849C>G

NC_000012.10:g.101834979C>G

NG_008690.1:g.5532G>C

NG_008690.2:g.46340G>C

NM_000277.1:c.60G>C

NM_001354304.1:c.60G>C

NM_000277.3:c.60G>C

ENST00000307000.7:c.-88G>C

ENST00000546844.1:c.60G>C

ENST00000547319.1:n.371G>C

ENST00000549111.5:n.156G>C

ENST00000550978.6:n.44G>C

ENST00000551337.5:c.60G>C

ENST00000551988.5:n.149G>C

ENST00000553106.5:c.60G>C

ENST00000635500.1:n.29-4173G>C

Uncertain Significance

PP3 PP4 PM2

PM3

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.60G>C (p.Q20H) variant has been reported in 1 patient with PKU (not excluding BH4 deficiency), who carried 2 pathogenic variants (p.R158Q, p.R408W) in PAH (PMID: 18321666, PMID: 23430918). This variant is absent from population databases, including 1000 Genomes, ESP, and gnomAD. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.571. In summary, this variant meets our criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PP4.

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP4

Reported in a PKU patient (Phe level 750, 2520). A urine sample was collected to look for putative abnormalities in biopterin metabolism. PMID: 18321666

The c.60G>C; p.Q20H variant was reported in a PKU patient (NL patient 1, Phe level 750, 2520). A urine sample was collected to look for putative abnormalities in biopterin metabolism. This patient has a third mutation (p.R408W) which can explain the absence of BH4 responsiveness despite the presence of 2 responsive mutations. PubMed:18321666

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM3

The c.60G>C; p.Q20H variant was reported a patient who carried a second pathogenic missense variant (p.R158Q). The patient has 3 variants per PMID: 18321666, with allele data unclear. PMID: 23430918

Unresponsive to sapropterin in a PKU patient with p.R158Q mutation. Supplementary table 1, patient 228 from Vandoeuvre les Nancy, France (same patient as PMID: 18321666) PubMed:23430918

The c.60G>C; p.Q20H variant was reported in a patient, who carried a second pathogenic missense variant (p.Arg158Gln; table 3). The trans variant is a two star pathogenic in ClinVar database. PubMed:18321666

Approved on: 2019-03-23

Published on: 2019-08-11

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