NM_000161.3(GCH1):c.140C>A (p.Ala47Glu) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 22, 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:: RCV001966392.6

Allele description [Variation Report for NM_000161.3(GCH1):c.140C>A (p.Ala47Glu)]

NM_000161.3(GCH1):c.140C>A (p.Ala47Glu)

Gene:

GCH1:GTP cyclohydrolase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q22.2

Genomic location:

Preferred name:

NM_000161.3(GCH1):c.140C>A (p.Ala47Glu)

HGVS:

NC_000014.9:g.54902524G>T
NG_008647.1:g.5301C>A
NM_000161.3:c.140C>AMANE SELECT
NM_001024024.2:c.140C>A
NM_001024070.2:c.140C>A
NM_001024071.2:c.140C>A
NP_000152.1:p.Ala47Glu
NP_001019195.1:p.Ala47Glu
NP_001019241.1:p.Ala47Glu
NP_001019242.1:p.Ala47Glu
NC_000014.8:g.55369242G>T

Protein change:

A47E

Links:

dbSNP: rs2040584415

NCBI 1000 Genomes Browser:

rs2040584415

Molecular consequence:

NM_000161.3:c.140C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001024024.2:c.140C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001024070.2:c.140C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001024071.2:c.140C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Dystonia 5 (DRD)
Synonyms:: Dystonia, progressive, with diurnal variation; Dystonia-Parkinsonism with diurnal fluctuation; Dystonia, DOPA-responsive, with or without hyperphenylalaninemia; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007495; MedGen: C1851920; Orphanet: 98808; OMIM: 128230

Name:: GTP cyclohydrolase I deficiency
Identifiers:: MONDO: MONDO:0100184; MedGen: C0268467

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002255504	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002255504

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 22, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002255504.3

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt GCH1 protein function. This variant has not been reported in the literature in individuals with GCH1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glutamic acid at codon 47 of the GCH1 protein (p.Ala47Glu). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and glutamic 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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