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.618C>A (p.Tyr206Ter)

CA6748887

556660 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 80b633ec-9aee-4b95-b50b-8e1c3adb5a72

HGVS expressions

NM_000277.3:c.618C>A

NM_000277.3(PAH):c.618C>A (p.Tyr206Ter)

NC_000012.12:g.102855224G>T

CM000674.2:g.102855224G>T

NC_000012.11:g.103249002G>T

CM000674.1:g.103249002G>T

NC_000012.10:g.101773132G>T

NG_008690.1:g.67379C>A

NG_008690.2:g.108187C>A

ENST00000553106.6:c.618C>A

ENST00000307000.7:c.603C>A

ENST00000549111.5:n.714C>A

ENST00000553106.5:c.618C>A

NM_000277.1:c.618C>A

NM_000277.2:c.618C>A

NM_001354304.1:c.618C>A

NM_001354304.2:c.618C>A

Pathogenic

PM2_Supporting PVS1 PM3_Strong PP4

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.618C>A (p.Tyr206Ter) is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 6/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. It has been detected in 4 patients with classic PKU with known pathogenic variants: c.611A>G (PMID: 16256386); p.Arg241Cys (PMID:25456745); and c.1197A>T p.Val399Val (PMID: 30050108). This variant has extremely low frequency in gnomAD (MAF=0.00005). In summary, this variant meets criteria to be classified as Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2_supporting, PM3_strong, PP4, PVS1.

PM2_Supporting

Variant identified in 1/18382 East Asian population which is at a frequency 0.00005 in gnomAD. The PM2 threshold set by the PAH VCEP is 0.0002.

PVS1

This is a nonsense variant that is 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)

PM3_Strong

In Chinese cohort, the variant was detected with c.611A>G (EX6-96A>G) which was classified as pathogenic in ClinVar. Phase unconfirmed. (PMID: 16256386) In another Chinese cohort, the variant was detected with c.721C>T (p.Arg241Cys) which is classified pathogenic in ClinVar. Phase was unconfirmed (PMID:25456745) In the South Chinese cohort, the variant was detected in trans c.1197A>T (p.Val399Val) which is classified pathogenic in ClinVar. (PMID: 26503515 30050108)

PP4

Detected in 3 patient with classic PKU. (PMID: 16256386 24130151 26503515 30050108) Detected in 1 patient with Phenylketonuria. (PMID: 25456745) Plasma phenylalanine > 120 umol/L

Approved on: 2023-10-13

Published on: 2023-10-13

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