NM_000277.3(PAH):c.615G>C (p.Glu205Asp) AND Phenylketonuria

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 2, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002000227.5

Allele description [Variation Report for NM_000277.3(PAH):c.615G>C (p.Glu205Asp)]

NM_000277.3(PAH):c.615G>C (p.Glu205Asp)

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.615G>C (p.Glu205Asp)

HGVS:

NC_000012.12:g.102855227C>G
NG_008690.2:g.108184G>C
NM_000277.1:c.615G>C
NM_000277.3:c.615G>CMANE SELECT
NM_001354304.2:c.615G>C
NP_000268.1:p.Glu205Asp
NP_001341233.1:p.Glu205Asp
NC_000012.11:g.103249005C>G

Protein change:

E205D

Links:

dbSNP: rs765552494

NCBI 1000 Genomes Browser:

rs765552494

Molecular consequence:

NM_000277.3:c.615G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.615G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Phenylketonuria (PKU)
Synonyms:: Phenylketonurias; Oligophrenia phenylpyruvica; Folling disease
Identifiers:: MONDO: MONDO:0009861; MedGen: C0031485; Orphanet: 716; OMIM: 261600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002233829	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 2, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11139255, 27121329, 22841515, 22112818, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002233829

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 2, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Ten novel mutations in the phenylalanine hydroxylase gene (PAH) observed in Brazilian patients with phenylketonuria.

Acosta AX, Silva WA Jr, Carvalho TM, Zago MA.

Hum Mutat. 2001;17(1):77.

PubMed [citation]

PMID:: 11139255

Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria.

Aldámiz-Echevarría L, Llarena M, Bueno MA, Dalmau J, Vitoria I, Fernández-Marmiesse A, Andrade F, Blasco J, Alcalde C, Gil D, García MC, González-Lamuño D, Ruiz M, Ruiz MA, Peña-Quintana L, González D, Sánchez-Valverde F, Desviat LR, Pérez B, Couce ML.

J Hum Genet. 2016 Aug;61(8):731-44. doi: 10.1038/jhg.2016.38. Epub 2016 Apr 28.

PubMed [citation]

PMID:: 27121329

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002233829.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu205 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11139255, 27121329, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. This variant has been observed in individual(s) with phenylketonuria (PMID: 22841515, 22112818). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with aspartic acid at codon 205 of the PAH protein (p.Glu205Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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