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_000277.3:c.843-13_843-10del

CA915940209

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 80f54968-5b4c-458b-b29f-f68fdeb98345

Approved on: 2022-05-27

Published on: 2022-06-28

HGVS expressions

NM_000277.3:c.843-13_843-10del

NC_000012.12:g.102851768_102851771del

CM000674.2:g.102851768_102851771del

NC_000012.11:g.103245546_103245549del

CM000674.1:g.103245546_103245549del

NC_000012.10:g.101769676_101769679del

NG_008690.1:g.70834_70837del

NG_008690.2:g.111642_111645del

ENST00000553106.6:c.843-13_843-10del

ENST00000307000.7:c.828-13_828-10del

ENST00000549247.6:n.602-13_602-10del

ENST00000551114.2:n.492_495del

ENST00000553106.5:c.843-13_843-10del

ENST00000635477.1:n.4-13_4-10del

NM_000277.1:c.843-13_843-10del

NM_000277.2:c.843-13_843-10del

NM_001354304.1:c.843-13_843-10del

NM_001354304.2:c.843-13_843-10del

Uncertain Significance

PM2 PP4_Moderate

PM3 PP3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.843-15_843-12del variant in PAH was reported in multiple Chinese patients with PAH deficiency (PMID: 26503515). The variant is referred to as ‘c.843-14_-11delCTTT’ in the paper. DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant is absent from the population databases ExAC and gnomAD. In silico models conflict on whether this variant breaks a splice donor site. In summary, this variant meets criteria to be classified as Uncertain Significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2 and PP4_moderate.

PM2

Absent from population databases gnomAD and ExAC.

PP4_Moderate

This variant (described in this paper as c.843-14_843-11del) was documented three times in Northern Chinese patients and once in a Southern Chinese patient (PMID: 26503515). Phenylalanine plasma concentrations >120 µmol/L were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay.

PM3

It was not specified whether patient genotypes were homozygous or compound heterozygous for the variant.

PP3

According to in silico splicing predictions, alteration potentially alters splicing. HSF (-18.7%) and MaxEnt (+4.84%) do not agree on whether this alteration of the WT donor site affects splicing.

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