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.434A>T (p.Asp145Val)

CA229539

102667 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 6ebfc9b5-513f-4058-98a8-49294b98dd36

HGVS expressions

NM_000277.2:c.434A>T

NM_000277.2(PAH):c.434A>T (p.Asp145Val)

NC_000012.12:g.102877469T>A

CM000674.2:g.102877469T>A

NC_000012.11:g.103271247T>A

CM000674.1:g.103271247T>A

NC_000012.10:g.101795377T>A

NG_008690.1:g.45134A>T

NG_008690.2:g.85942A>T

NM_000277.1:c.434A>T

NM_001354304.1:c.434A>T

NM_000277.3:c.434A>T

ENST00000307000.7:c.419A>T

ENST00000549111.5:n.530A>T

ENST00000550978.6:n.418A>T

ENST00000551988.5:n.523A>T

ENST00000553106.5:c.434A>T

Likely Pathogenic

PM3_Strong PP3 PP4_Moderate PM2

PM5

Evidence Links 7

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.434A>T (p.Asp145Val) PAH variant has been identified in patients with PAH deficiency from the US, Germany, Italy and Spain. BH4 deficiency was excluded. (PMID: 8659548; 11385716; 12655553; 17096675; 23514811) It was detected with known pathogenic variants: V388M (PMID: 8659548), I65T (PMID: 24368688), and R408W (PMID: 26666653). It is found at extremely low frequency (MAF 0.00012 in gnomAD). A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.987. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3

PM3_Strong

Detected with known pathogenic variants: V388M (PMID: 8659548), I65T (PMID: 24368688), and R408W (PMID: 26666653).

Patient 8 genotype: p.I65T/p.D145V PubMed:24368688

Patient I/1140/LMA-10: Allele1: D145V, Allele 2: V388M (Pathogenic in ClinVar). PubMed:8659548

Genotype: c. [434A>T]; [1222C>T]/p. [Asp145Val];[Arg408Trp] PubMed:26666653

PP3

Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.987

PP4_Moderate

D145V has been identified patients with PAH deficiency from the US, Germany, Italy and Spain. BH4 deficiency excluded. PMID: 8659548; 11385716; 12655553; 17096675; 23514811.

Forty newborns ascertained by the Texas Newborn Screening Program due to phenylalanine (PHE) levels in serum above 4 mg/dl were blinded and studied. The diagnosis of classic PKU was done in cases with the untreated level of PHE > 20 mg/dl (1200 μM), normal level of Biopterin and the tyrosine level < 3 mg/dl. D145V identified on 1 chromosome. PubMed:11385716

126 HPA patients from Southern Italy who were identified in a neonatal screening program. D145V identified in a mild HPA patient. PubMed:17096675

226 German families with PAH deficiency, most of them from Southern Germany. D145V seen on 2 alleles. PubMed:12655553

149 hyperphenylalaninemic females were diagnosed by blood Phe, blood tyrosine, and metabolites in urine. D145V identified in 1 patient with MHP (380 umol/l). PubMed:8659548

We detected in this period 179 patients (78 male and 91 female) of the Andalusian community whose cut-off value for phenylalanine is 180 mM. Patients with transient HPA (two patients) or with HPA due to a defect in the synthesis or recycling of the cofactor BH4 (two patients) were excluded. D145V seen on 1 allele. PubMed:23514811

PM2

Extremely low frequency: MAF 0.00012 in gnomAD.

PM5

only variant found in this codon in ClinVar

Approved on: 2018-12-10

Published on: 2019-04-06

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