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]

Variant: NM_000277.1:c.875C>T

CA16020882

626282 (ClinVar)

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 3f9695f4-a4fc-4c00-af32-1cac6e4e001f

Approved on: 2020-06-26

Published on: 2020-06-26

HGVS expressions

NM_000277.1:c.875C>T

NC_000012.12:g.102851724G>A

CM000674.2:g.102851724G>A

NC_000012.11:g.103245502G>A

CM000674.1:g.103245502G>A

NC_000012.10:g.101769632G>A

NG_008690.1:g.70879C>T

NG_008690.2:g.111687C>T

NM_000277.2:c.875C>T

NM_001354304.1:c.875C>T

NM_000277.3:c.875C>T

NM_001354304.2:c.875C>T

ENST00000307000.7:c.860C>T

ENST00000549247.6:n.634C>T

ENST00000551114.2:n.537C>T

ENST00000553106.5:c.875C>T

ENST00000635477.1:n.36C>T

Likely Pathogenic

PM3_Strong PP4_Moderate PP3 PM2

Evidence Links 5

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.875C>T (p.Pro292Leu) variant in PAH has been reported in multiple individuals with mild PKU (BH4 deficiency excluded). (PMID: 26503515, 24705691, 29413232). This variant has extremely low frequency in gnomAD (MAF=0.00006). This variant was detected in trans with pathogenic variants c.913-7A>G (PMID: 26322415) and p.Arg243Gln (PMID: 31178897). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3.

PM3_Strong

Detected in trans with c.913-7A>G (LP) confirmed by analyzing parental DNA PMID: 26322415 and p.Arg243Gln detected with Trio-WES (P 10 submitters) PMID: 31178897

PubMed:31178897

PubMed:26322415

PP4_Moderate

Seen in multiple patients with PKU in 3 studies. One study mentioned BH4 deficiency excluded. PMID: 26503515, PMID: 24705691, PMID: 29413232

Seen in an individual with PAH-defecient PKU, Methods state serum Phe concentrations ofthese patients fell in a range from 360 mmol/L to 1800 mmol/L. PubMed:29413232

Seen in a individual with diagnosed PKU, no other information provided. From a 'core' family meaning a completed pedigree. No consanguineous families were included in this study PubMed:24705691

Seen in an individual with PKU. A total of 796 unrelated patients from 29 separate newborn screening centres of China were enrolled. These patients were diagnosed at birth either through a neonatal screening program or based on clinical presentation. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. PubMed:26503515

PP3

Multiple lines predict deleterious effect. Predicted deleterious by SIFT, probably damaging by Polyphen and Disease causing by MutationTaster.

PM2

Absent from 1000G and Exac. Low freq in gnomAD (MAF=0.00006)

Curation History

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