Evidence Repository
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_000277.1:c.971T>A

CA10602335

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 43243d0e-d5fb-4550-9585-d6c1913c3448
Approved on: 2023-12-30
Published on: 2023-12-30

HGVS expressions

NM_000277.1:c.971T>A
NC_000012.12:g.102844430A>T
CM000674.2:g.102844430A>T
NC_000012.11:g.103238208A>T
CM000674.1:g.103238208A>T
NC_000012.10:g.101762338A>T
NG_008690.1:g.78173T>A
NG_008690.2:g.118981T>A
ENST00000553106.6:c.971T>A
ENST00000307000.7:c.956T>A
ENST00000549247.6:n.730T>A
ENST00000551114.2:n.633T>A
ENST00000553106.5:c.971T>A
ENST00000635477.1:c.75T>A
ENST00000635528.1:n.486T>A
NM_000277.2:c.971T>A
NM_001354304.1:c.971T>A
NM_000277.3:c.971T>A
NM_001354304.2:c.971T>A

Pathogenic

Met criteria codes 4
PM2_Supporting PP4_Moderate PP3 PM3_Very Strong
Not Met criteria codes 1
PS3

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The NM_000277.3:c.971T>A (p.Ile324Asn) variant is a missense variant in exon 10 of 13 of PAH. It has been previously reported in at least 12 patients with PKU and BH4 deficiency formally excluded, including in confirmed trans with Pathogenic or Likely Pathogenic variants (PM3_VeryStrong (7.5 points total); PP4_Moderate). It was reported in presumed trans with p.R241C (Pathogenic per ClinGen PAH VCEP) in a Chinese proband with mild PKU (plasma Phe 760 μmol/L) and BH4 deficiency was said to be excluded (PMID: 28982351); in presumed trans with p.R111* (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU and in presumed trans with c.509+1G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU (plasma Phe levels not specified; BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes). It has also been reported in confirmed trans with c.1066-11G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with PKU and BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 24705691); in a Chinese proband with PKU in confirmed trans with the c.442–1G>A variant (Pathogenic by ClinGen PAH VCEP) and in another Chinese proband with PKU in confirmed trans with the p.G247R variant (Likely Pathogenic by ClinGen PAH VCEP) (PMID: 29353259). It has been noted in a patient with PKU in presumed trans with p.T418P variant (Pathogenic by ClinGen PAH VCEP) (plasma Phe levels not noted; BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 29731766); in a Chinese patient with mild PKU (plasma Phe 780 umol/L) in presumed trans with the p.R243Q variant (Pathogenic by ClinGen PAH VCEP) and BH4 deficiency excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 28754886). Finally, it has been noted among multiple Chinese PKU patients with BH4 deficiency excluded by urinary pterin analysis, including in the homozygous state in a Chinese patient with classic PKU (plasma Phe not noted), in another patient with PKU (phenotype not further specified) in presumed trans with the c.611A>G (p.Ex6-96A>G) variant (Pathogenic by ClinGen PAH VCEP), in presumed trans with the p.V399V variant (Pathogenic by ClinGen PAH VCEP) in another Chinese patient with mild PKU, and in presumed trans with the p.Y356* variant (Pathogenic by ClinGen PAH VCEP) (PMID: 30050108). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.889) (PP3). Classification: Pathogenic Supporting Criteria: PM3_VeryStrong; PM2_supporting; PP4_Moderate; PP3
Met criteria codes
PM2_Supporting
Not found in gnomAD v2.1.1
PP4_Moderate
It has been previously reported in at least 12 patients with PKU and BH4 deficiency formally excluded, including in confirmed trans with Pathogenic or Likely Pathogenic variants (PM3_VeryStrong (7.5 points total); PP4_Moderate). It was reported in presumed trans with p.R241C (Pathogenic per ClinGen PAH VCEP) in a Chinese proband with mild PKU (plasma Phe 760 μmol/L) and BH4 deficiency was said to be excluded (PMID: 28982351); in presumed trans with p.R111* (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU and in presumed trans with c.509+1G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU (plasma Phe levels not specified; BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes). It has also been reported in confirmed trans with c.1066-11G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with PKU and BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 24705691); in a Chinese proband with PKU in confirmed trans with the c.442–1G>A variant (Pathogenic by ClinGen PAH VCEP) and in another Chinese proband with PKU in confirmed trans with the p.G247R variant (Likely Pathogenic by ClinGen PAH VCEP) (PMID: 29353259). It has been noted in a patient with PKU in presumed trans with p.T418P variant (Pathogenic by ClinGen PAH VCEP) (plasma Phe levels not noted; BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 29731766); in a Chinese patient with mild PKU (plasma Phe 780 umol/L) in presumed trans with the p.R243Q variant (Pathogenic by ClinGen PAH VCEP) and BH4 deficiency excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 28754886). Finally, it has been noted among multiple Chinese PKU patients with BH4 deficiency excluded by urinary pterin analysis, including in the homozygous state in a Chinese patient with classic PKU (plasma Phe not noted), in another patient with PKU (phenotype not further specified) in presumed trans with the c.611A>G (p.Ex6-96A>G) variant (Pathogenic by ClinGen PAH VCEP), in presumed trans with the p.V399V variant (Pathogenic by ClinGen PAH VCEP) in another Chinese patient with mild PKU, and in presumed trans with the p.Y356* variant (Pathogenic by ClinGen PAH VCEP) (PMID: 30050108).
BH4 defect excluded with urine pterins and DHPR activity. Single patient with this variant. PubMed:26322415
BH4 defect excluded via sequencing of all genes associated with primary BH4 defects. Single patient PubMed:24705691
PP3
All computational evidence suggests damaging effect. REVEL=0.889
PM3_Very Strong
It has been previously reported in at least 12 patients with PKU and BH4 deficiency formally excluded, including in confirmed trans with Pathogenic or Likely Pathogenic variants (PM3_VeryStrong (7.5 points total); PP4_Moderate). It was reported in presumed trans with p.R241C (Pathogenic per ClinGen PAH VCEP) in a Chinese proband with mild PKU (plasma Phe 760 μmol/L) and BH4 deficiency was said to be excluded (PMID: 28982351); in presumed trans with p.R111* (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU and in presumed trans with c.509+1G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU (plasma Phe levels not specified; BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes). It has also been reported in confirmed trans with c.1066-11G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with PKU and BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 24705691); in a Chinese proband with PKU in confirmed trans with the c.442–1G>A variant (Pathogenic by ClinGen PAH VCEP) and in another Chinese proband with PKU in confirmed trans with the p.G247R variant (Likely Pathogenic by ClinGen PAH VCEP) (PMID: 29353259). It has been noted in a patient with PKU in presumed trans with p.T418P variant (Pathogenic by ClinGen PAH VCEP) (plasma Phe levels not noted; BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 29731766); in a Chinese patient with mild PKU (plasma Phe 780 umol/L) in presumed trans with the p.R243Q variant (Pathogenic by ClinGen PAH VCEP) and BH4 deficiency excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 28754886). Finally, it has been noted among multiple Chinese PKU patients with BH4 deficiency excluded by urinary pterin analysis, including in the homozygous state in a Chinese patient with classic PKU (plasma Phe not noted), in another patient with PKU (phenotype not further specified) in presumed trans with the c.611A>G (p.Ex6-96A>G) variant (Pathogenic by ClinGen PAH VCEP), in presumed trans with the p.V399V variant (Pathogenic by ClinGen PAH VCEP) in another Chinese patient with mild PKU, and in presumed trans with the p.Y356* variant (Pathogenic by ClinGen PAH VCEP) (PMID: 30050108).
Single patient with this allele c.971T>A / c.331C>T (R111*) pathogenic with "classic PKU", but no specific Phe levels listed. PubMed:26322415
Patient #7 I324N / R243Q with moderate PKU (720-780umol/L Phe) PubMed:24327145
Not Met criteria codes
PS3
In vitro expression analysis shows PAH activity of 50.6% PMID: 24327145
In vitro expression analysis shows PAH activity of 50.6% PubMed:24327145
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