Variant: NM_000277.3(PAH):c.970-6T>G

CA229884

102920 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: 9a912841-3d1c-4671-9f82-163b43e0a969

Approved on: 2020-07-09

Published on: 2022-06-28

HGVS expressions

NM_000277.3:c.970-6T>G
NM_000277.3(PAH):c.970-6T>G
NC_000012.12:g.102844437A>C
CM000674.2:g.102844437A>C
NC_000012.11:g.103238215A>C
CM000674.1:g.103238215A>C
NC_000012.10:g.101762345A>C
NG_008690.1:g.78166T>G
NG_008690.2:g.118974T>G
ENST00000553106.6:c.970-6T>G
ENST00000307000.7:c.955-6T>G
ENST00000549247.6:n.729-6T>G
ENST00000551114.2:n.632-6T>G
ENST00000553106.5:c.970-6T>G
ENST00000635477.1:n.74-6T>G
ENST00000635528.1:n.485-6T>G
NM_000277.1:c.970-6T>G
NM_000277.2:c.970-6T>G
NM_001354304.1:c.970-6T>G
NM_001354304.2:c.970-6T>G

Uncertain Significance

• Met criteria codes: PP3 PM3 PM2

• Not Met criteria codes: PP4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.970-6T>G variant in PAH is absent from population databases (PM2). It has been observed in at least one PKU patient (PMID: 7766957) compound heterozygous with pathogenic variant R413P (ClinVar592; PM3). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3.

Met criteria codes

• PP3: MaxEntScan predicts alteration of the WT Donor site, most probably affecting splicing (7.71 > 1.25=> -83.79%). SpliceAI: Splice-Altering (0.57). TraP Score: 0.695 (>99%). The nucleotide is highly conserved (PhyloP score 2.06).
• PM3: PMID: 7766957 reports Patient B compound heterozygous for c.970-6T>G and R413P (ClinVar592 Pathogenic), with trans phasing confirmed through cloning.
• PM2: The c.969+6T>C variant is absent from population databases including gnomAD, ExAC, 1000 Genomes, and ESP.

Not Met criteria codes

• PP4: PMID: 7766957 reports Patient B with phenylketonuria but provides no further information on phenotype.