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(PAH):c.222A>G (p.Lys74=)

CA6748996

991624 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d9babc72-4602-44c1-89e9-9f52aadc92ba

HGVS expressions

NM_000277.3:c.222A>G

NM_000277.3(PAH):c.222A>G (p.Lys74=)

NC_000012.12:g.102894865T>C

CM000674.2:g.102894865T>C

NC_000012.11:g.103288643T>C

CM000674.1:g.103288643T>C

NC_000012.10:g.101812773T>C

NG_008690.1:g.27738A>G

NG_008690.2:g.68546A>G

ENST00000553106.6:c.222A>G

ENST00000307000.7:c.207A>G

ENST00000546844.1:c.222A>G

ENST00000548677.2:n.309A>G

ENST00000548928.1:n.144A>G

ENST00000549111.5:n.318A>G

ENST00000550978.6:n.206A>G

ENST00000551337.5:c.222A>G

ENST00000551988.5:n.311A>G

ENST00000553106.5:c.222A>G

NM_000277.1:c.222A>G

NM_000277.2:c.222A>G

NM_001354304.1:c.222A>G

NM_001354304.2:c.222A>G

Uncertain Significance

BS1 BP7 PM2

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The NM_000277.3:c.222A>G variant in PAH is a synonymous (silent) variant (p.Lys74=) that is not predicted to impact splicing. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0003204 (8/24966 alleles) in the African/African American population (none of the population data codes are met). There is a ClinVar entry for this variant (Variation ID: 991624, 1 star review status) with one submitter classifying the variant as a variant of uncertain significance and one submitter classifying the variant as likely benign. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): no criteria are met.

BS1

The highest population minor allele frequency in gnomAD v2.1.1 is 0.0003204 (8/24966 alleles) in the African/African American population (none of the population data codes are met).

BP7

synonymous (silent) variant (p.Lys74=) that is not predicted to impact splicing but nucleotide is conserved from humans through X.Tropicalis

PM2

The highest population minor allele frequency in gnomAD v2.1.1 is 0.0003204 (8/24966 alleles) in the African/African American population (none of the population data codes are met).

Approved on: 2023-07-23

Published on: 2023-07-23

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