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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000277.2(PAH):c.307G>T (p.Gly103Cys)

CA6748984

553638 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 508f9867-dc09-41bb-897d-7936dd45c772

HGVS expressions

NM_000277.2:c.307G>T

NM_000277.2(PAH):c.307G>T (p.Gly103Cys)

NC_000012.12:g.102894780C>A

CM000674.2:g.102894780C>A

NC_000012.11:g.103288558C>A

CM000674.1:g.103288558C>A

NC_000012.10:g.101812688C>A

NG_008690.1:g.27823G>T

NG_008690.2:g.68631G>T

ENST00000553106.6:c.307G>T

ENST00000307000.7:c.292G>T

ENST00000546844.1:c.307G>T

ENST00000548928.1:n.229G>T

ENST00000549111.5:n.403G>T

ENST00000550978.6:n.291G>T

ENST00000551337.5:c.307G>T

ENST00000551988.5:n.396G>T

ENST00000553106.5:c.307G>T

NM_000277.1:c.307G>T

NM_001354304.1:c.307G>T

NM_000277.3:c.307G>T

NM_001354304.2:c.307G>T

NM_000277.3(PAH):c.307G>T (p.Gly103Cys)

Uncertain Significance

PP4 PM2_Supporting PP3_Moderate PM3_Supporting

PM5

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.307G>T (p.Gly103Cys) variant in PAH has been reported in 2 patients with PKU (BH4 deficiency not assessed/reported) (PP4; PMID: 17502162, 24368688). It was detected in unknown phase with a pathogenic variant c.1066-11G>A (PMID: 17502162) and a likely pathogenic variant p.Y154F (PMID: 24368688). This variant has extremely low frequency in ExAC (MAF=0.00001). Computational evidence supports a deleterious effect (REVEL=0.819). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2_supporting, PM3_supporting, PP3_moderate.

PP4

c.307G>T was identified in 1 patient with PKU. Bh4 deficiency not assessed/reported. PMID: 17502162

Twenty original newborn screening DBS specimens were recovered from an archive. Blood was collected on filter paper from 46 patients followed at Children’s Hospital of Boston and from 29 patients followed at the University of Southern California School of Medicine. Table 5. Sample 37: c.307G>T was identified on allele 2. PubMed:17502162

PM2_Supporting

Extremely low frequency in gnomAD (MAF=0.000008793). Filtered variant: failed RF filter.

PP3_Moderate

SIFT (T), PolyPhen-2 (D,P), MutationTaster (D), REVEL=0.819.

PM3_Supporting

Detected with c.1066-11G>A (known pathogenic variant) PMID: 17502162; and p.Y154F (LP) PMID: 24368688. phase unknown. 0.75 points

Table 5. Sample 37. allele 1: c.1066-11G>A/ allele 2; c.307G>T. PubMed:17502162

Table 1. Patient 97. Allele 1: c.307G>T/ Allele 2: c.461A>T (p.Y154F) Novel. PubMed:24368688

PM5

G103D (VUS by PAH VCEP), G103S (LP by PAH VCEP)

Approved on: 2023-07-23

Published on: 2023-07-23

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