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_000277.2(PAH):c.441+6T>A

CA267654

120275 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f4d1a114-f822-49f7-aec3-f445c0174a02

HGVS expressions

NM_000277.2:c.441+6T>A

NM_000277.2(PAH):c.441+6T>A

NC_000012.12:g.102877456A>T

CM000674.2:g.102877456A>T

NC_000012.11:g.103271234A>T

CM000674.1:g.103271234A>T

NC_000012.10:g.101795364A>T

NG_008690.1:g.45147T>A

NG_008690.2:g.85955T>A

NM_000277.1:c.441+6T>A

NM_001354304.1:c.441+6T>A

NM_000277.3:c.441+6T>A

ENST00000307000.7:c.426+6T>A

ENST00000549111.5:n.537+6T>A

ENST00000550978.6:n.431T>A

ENST00000551988.5:n.530+6T>A

ENST00000553106.5:c.441+6T>A

Likely Pathogenic

PM2 PP4_Moderate PM3_Strong PP3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.441+6T>A variant in PAH has been reported in at least 2 patients with PKU (BH4 deficiency ruled out), who carried pathogenic variants (ClinVar IDs: 589 & 576) (PMID: 22526846). This variant is absent from 1000G and ESP, and has an extremely low frequency in gnomAD (MAF= 0.000004). This intronic variant changes a moderately conserved nucleotide, and computational analyses (Alamut) predict that this variant may weaken (~60%) the splice donor site of intron 4. Based on the available information, this variant is considered to be likely pathogenic. PAH-specific ACMG/AMP criteria applied: PP3, PP4_M, PM2, PM3_S.

PM2

gnomAD MAF 0.000004

PP4_Moderate

Patient 95: BH4 deficiency ruled out; Phe 900 uM. (Supplemental table 1)

Patient 95: BH4 deficiency ruled out; Phe 900 uM. (Supplemental table 1) PubMed:22526846

PM3_Strong

Detected in trans with likely pathogenic p.P281L (ClinVar 589) family segregation performed, and c.1315+1G>A (ClinVar 576).

Detected in trans with likely pathogenic p.P281L (ClinVar 589), and c.1315+1G>A (ClinVar 576). Family segregation was consistent with autosomal recessive inheritance. PubMed:22526846

PP3

Alamut predictors: reduces ~60% the donor site of exon 4/intron 4.

Approved on: 2019-08-06

Published on: 2019-08-07

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