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.194T>A (p.Ile65Asn)

Curation Version - 1.0
Curation History
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CA229479

102623 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a1719899-148c-4be8-9193-1d376d4059d9

Approved on: 2018-12-09

Published on: 2019-04-06

HGVS expressions

NM_000277.2:c.194T>A

NM_000277.2(PAH):c.194T>A (p.Ile65Asn)

NC_000012.12:g.102894893A>T

CM000674.2:g.102894893A>T

NC_000012.11:g.103288671A>T

CM000674.1:g.103288671A>T

NC_000012.10:g.101812801A>T

NG_008690.1:g.27710T>A

NG_008690.2:g.68518T>A

NM_000277.1:c.194T>A

NM_001354304.1:c.194T>A

NM_000277.3:c.194T>A

ENST00000307000.7:c.179T>A

ENST00000546844.1:c.194T>A

ENST00000548677.2:n.281T>A

ENST00000548928.1:n.116T>A

ENST00000549111.5:n.290T>A

ENST00000550978.6:n.178T>A

ENST00000551337.5:c.194T>A

ENST00000551988.5:n.283T>A

ENST00000553106.5:c.194T>A

ENST00000635500.1:n.162T>A

Likely Pathogenic

PP3 PM3 PM2 PP4_Moderate

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.194T>A (p.Ile65Asn) variant was identified in a patient with classic PKU. BH4 deficiency was ruled out. (PMID: 9521426). It was detected in trans with known pathogenic mutation c.143T>C (p.L48S). It has an extremely low frequency in PAGE (0.00026); and is absent from ExAC, 1000 Genomes, gnomAD. Multiple lines of computational evidence support a deleterious effect (SIFT, Polyphen-2, MutationTaster; REVEL=0.957). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate, PP3.

PP3

Multiple lines of computational evidence support a deleterious effect (SIFT, Polyphen-2, MutationTaster; REVEL=0.957).

PM3

c.194T>A (p.I65N) was detected in trans with known pathogenic mutation c.143T>C (p.L48S). PMID: 9521426

c.194T>A (p.I65N) was identified in trans to the known c.143T>C (L48S) mutation in a patient with classic PKU. Segregation was tested for seven of the eight new mutations by DGGE (DG) and/or DNA sequencing(DS) and/or enzymatic digestion (ED). Parental origin of I65N could not be ascertained because the father’s DNA was not available. PubMed:9521426

PM2

Extremely low frequency in PAGE (0.00026); Absent from ExAC, 1000 Genomes, gnomAD.

PP4_Moderate

c.194T>A (p.I65N) was identified in a patient with classic PKU. BH4 deficiency ruled out. PMID: 9521426

c.194T>A (p.I65N) was identified in trans to the known c.143T>C (L48S) mutation in patient F18 with classic PKU. The occurrence of defects involving homeostasis or synthesis of the phenylalanine hydroxylase cofactor (BH4) was ruled out by dosing the urinary pterins. PubMed:9521426

Curation History

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