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.1304A>T (p.Asp435Val)

CA386492936

625291 (ClinVar)

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 5f40c3bc-a96c-4619-bf95-57c324cff700

Approved on: 2020-04-10

Published on: 2020-04-10

HGVS expressions

NM_000277.3(PAH):c.1304A>T (p.Asp435Val)

NM_000277.3:c.1304A>T

NC_000012.12:g.102840411T>A

CM000674.2:g.102840411T>A

NC_000012.11:g.103234189T>A

CM000674.1:g.103234189T>A

NC_000012.10:g.101758319T>A

NG_008690.1:g.82192A>T

NG_008690.2:g.123000A>T

NM_000277.1:c.1304A>T

NM_000277.2:c.1304A>T

NM_001354304.1:c.1304A>T

NM_001354304.2:c.1304A>T

ENST00000307000.7:c.1289A>T

ENST00000551114.2:n.966A>T

ENST00000553106.5:c.1304A>T

ENST00000635477.1:n.408A>T

ENST00000635528.1:n.819A>T

Likely Pathogenic

PP4_Moderate PM2 PM3

PP3

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1304A>T (p.Asp435Val) variant in PAH has been reported in a Uygur patient with moderate PKU (BH4 deficiency ruled out) (PP4_Moderate; PMID: 31355225). This variant was detected with p.Ala434Asp (Likely pathogenic in ClinVar) (PM3; PMID: 31355225). The variant is absent from population databases (PM2). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate.

PP4_Moderate

PMID: 31355225 - PCR and Sanger sequencing detected D435V in an Uygur patient with moderate PKU (Phe = 360-1200umol/L), BH4 deficiency ruled out

PubMed:31355225

PM2

Variant absent from population databases

PM3

PMID: 31355225 - Patient 108 carried the previously described variant p.Ala434Asp (VarID 102586, LP, 2 submitters), parents were tested - variants confirmed in trans - 1.0 points

PubMed:31332730

PP3

Variant predicted to be tolerated by SIFT, benign by PolyPhen2, disease causing by MutationTaster, and REVEL = 0.707.

Curation History

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