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NM_000277.3(PAH):c.442G>C (p.Gly148Arg) AND Phenylketonuria

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Sep 6, 2024
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001093506.2

Allele description [Variation Report for NM_000277.3(PAH):c.442G>C (p.Gly148Arg)]

NM_000277.3(PAH):c.442G>C (p.Gly148Arg)

Gene:
PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12q23.2
Genomic location:
Preferred name:
NM_000277.3(PAH):c.442G>C (p.Gly148Arg)
HGVS:
  • NC_000012.12:g.102866663C>G
  • NG_008690.2:g.96748G>C
  • NM_000277.3:c.442G>CMANE SELECT
  • NM_001354304.2:c.442G>C
  • NP_000268.1:p.Gly148Arg
  • NP_001341233.1:p.Gly148Arg
  • NC_000012.11:g.103260441C>G
Protein change:
G148R
Links:
dbSNP: rs80297647
NCBI 1000 Genomes Browser:
rs80297647
Molecular consequence:
  • NM_000277.3:c.442G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.442G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Phenylketonuria (PKU)
Synonyms:
FOLLING DISEASE; OLIGOPHRENIA PHENYLPYRUVICA; Phenylketonurias
Identifiers:
MONDO: MONDO:0009861; MedGen: C0031485; Orphanet: 716; OMIM: 261600

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001250529ClinGen PAH Variant Curation Expert Panel
reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)		Likely Pathogenic
(Sep 6, 2024) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen PAH Variant Curation Expert Panel, SCV001250529.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.442G>C (p.Gly148Arg) variant in PAH is a missense variant that is predicted damaging by REVEL (REVEL score 0.947) (PP3_Strong). It is absent from gnomAD v2.1.1 (PM2_Supporting). It has been reported in at least 1 Chinese patient with PAH deficiency with BH4 deficiency excluded (PMID: 26503515, 30050108) (PP4_Moderate), and has been reported in unknown phase with the pathogenic variant p.Arg243Gln (ClinVar ID: 591) (PM3_Supporting). Multiple different missense variants at the same site have been reported likely pathogenic in ClinVar, including c.443G>A (p.Gly148Asp) (ClinVar ID: 872837), c.443G>T (p.Gly148Val) (ClinVar ID: 552657), c.442G>A (p.Gly148Ser) (ClinVar ID: 102680) (PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: PM2_Supporting, PM5_Supporting, PP4_Moderate, PP3_Strong.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 13, 2025