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_000277.3(PAH):c.586_608del (p.Ser196fs)

CA229634

102743 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 3c726e17-eac3-4375-af90-eceffdbcb7df

HGVS expressions

NM_000277.3:c.586_608del

NM_000277.3(PAH):c.586_608del (p.Ser196fs)

NM_000277.1:c.586_608del

NM_000277.2:c.586_608del

NM_001354304.1:c.586_608del

NM_001354304.2:c.586_608del

ENST00000307000.7:c.571_593del

ENST00000549111.5:n.682_704del

ENST00000553106.5:c.586_608del

NC_000012.12:g.102855235_102855257del

CM000674.2:g.102855235_102855257del

NC_000012.11:g.103249013_103249035del

CM000674.1:g.103249013_103249035del

NC_000012.10:g.101773143_101773165del

NG_008690.1:g.67347_67369del

NG_008690.2:g.108155_108177del

Pathogenic

PM3 PM2 PP4_Moderate PVS1

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.586_608del (p.Ser196fs) frameshift variant in PAH is predicted to undergo nonsense-mediated decay. This variant was reported in a Spanish patient with classic PKU in trans with pathogenic variant p.Arg261Gln. A defect in the synthesis or regeneration in the pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and by measuring the dihydropteridine reductase activity (PMID 27121329). This variant was also reported in another Spanish patient with moderate PKU and identified with the pathogenic variant p.I65T (PMID 15464430). This variant is absent from gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, and PP4 moderate.

PM3

Detected in trans with pathogenic variant p.Arg261Gln. Segregation analysis was done (PMID 27121329). Heterozygous with pathogenic variant p.I65T and Mendelian inheritance was confirmed in all cases by DGGE or sequencing analysis. (PMID 15464430).

PubMed:27121329

PM2

Absent from gnomAD.

PP4_Moderate

Reported in a Spanish patient with classic PKU. A defect in the synthesis or regeneration in the pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity (PMID 27121329). Reported in a second Spanish patient with moderate PKU. Urinary pterin analysis and DHPR activity measurements excluded a BH4 deficiency in these cases (PMID 15464430).

PVS1

Frameshift variant, predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 6 out of 13 coding exons (6 out of total exons)

Approved on: 2020-07-24

Published on: 2020-07-24

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