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.301G>A (p.Asp101Asn)

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CA16020762

553851 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d22e7b49-130c-409a-8c8c-270cdd072c23

Approved on: 2020-04-10

Published on: 2020-04-10

HGVS expressions

NM_000277.2:c.301G>A

NM_000277.2(PAH):c.301G>A (p.Asp101Asn)

NC_000012.12:g.102894786C>T

CM000674.2:g.102894786C>T

NC_000012.11:g.103288564C>T

CM000674.1:g.103288564C>T

NC_000012.10:g.101812694C>T

NG_008690.1:g.27817G>A

NG_008690.2:g.68625G>A

NM_000277.1:c.301G>A

NM_001354304.1:c.301G>A

NM_000277.3:c.301G>A

NM_001354304.2:c.301G>A

ENST00000307000.7:c.286G>A

ENST00000546844.1:c.301G>A

ENST00000548928.1:n.223G>A

ENST00000549111.5:n.397G>A

ENST00000550978.6:n.285G>A

ENST00000551337.5:c.301G>A

ENST00000551988.5:n.390G>A

ENST00000553106.5:c.301G>A

Likely Pathogenic

PM2 PM3_Strong PP4_Moderate

PP3

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.301G>A (p.Asp101Asn) variant in PAH has been reported in 3 patients with PKU (BH4 deficiency excluded) (PMID: 26503515, 26600521, 28982351). This variant is absent from controls in ExAC, gnomAD, 1000 Genomes, ESP. Conflicting computational evidence: SIFT (T); PolyPhen-2 (B); MutationTaster (D); REVEL=0.465. It is detected in trans with pathogenic variants Q267E and p.Arg158Trp. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong.

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, ESP

PM3_Strong

Detected in trans with Q267E (P, PAH VCEP) PMID: 26600521 p.Arg158Trp (P, 4 submitters) . PMID: 28982351 variable sites in patient genes were aligned with the corresponding sites from the respective parents

Table 4. Family 86. Proband genotype: D101N/Q267E (VarID102839, no clinical significance provided) PubMed:26600521

PubMed:28982351

PP4_Moderate

p.D101N (c.301G>A) was detected in 3 patients with PKU. BH4 deficiency assessed. PMID: 26503515

A total of 796 unrelated patients from 29 separate newborn screening centres of China were enrolled. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. p.D101N (c.301G>A) was detected in 1 patient. PubMed:26503515

PP3

Conflicting computational evidence: SIFT (T); PolyPhen-2 (B); MutationTaster (D); REVEL=0.465.

Curation History

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