NM_000159.4(GCDH):c.554G>A (p.Gly185Glu) AND Glutaric aciduria, type 1

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 28, 2023
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:: RCV003838014.2

Allele description [Variation Report for NM_000159.4(GCDH):c.554G>A (p.Gly185Glu)]

NM_000159.4(GCDH):c.554G>A (p.Gly185Glu)

Gene:

GCDH:glutaryl-CoA dehydrogenase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.13

Genomic location:

Preferred name:

NM_000159.4(GCDH):c.554G>A (p.Gly185Glu)

HGVS:

NC_000019.10:g.12896040G>A
NG_009292.1:g.9881G>A
NM_000159.4:c.554G>AMANE SELECT
NM_013976.5:c.554G>A
NP_000150.1:p.Gly185Glu
NP_039663.1:p.Gly185Glu
NC_000019.9:g.13006854G>A
NR_102316.1:n.717G>A
NR_102317.1:n.970G>A

Protein change:

G185E

Molecular consequence:

NM_000159.4:c.554G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_013976.5:c.554G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_102316.1:n.717G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_102317.1:n.970G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Glutaric aciduria, type 1
Synonyms:: GA I; Glutaryl-CoA dehydrogenase deficiency; Glutaric acidemia type I; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009281; MedGen: C0268595; Orphanet: 25; OMIM: 231670

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Mus musculus adult male testis cDNA, RIKEN full-length enriched library, clone:1...
Mus musculus adult male testis cDNA, RIKEN full-length enriched library, clone:1700061I17 product:hypothetical protein, full insert sequence
gi|12840131|dbj|AK006854.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004631096	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24332224, 29292490, 29665094, 31737040, 34306040, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004631096

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 28, 2023)

germline

clinical testing

PubMed (6)
[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

Clinical and mutational spectra of 23 Chinese patients with glutaric aciduria type 1.

Wang Q, Li X, Ding Y, Liu Y, Song J, Yang Y.

Brain Dev. 2014 Oct;36(9):813-22. doi: 10.1016/j.braindev.2013.11.006. Epub 2013 Dec 9.

PubMed [citation]

PMID:: 24332224

Two Uneventful Pregnancies in a Woman with Glutaric Aciduria Type 1.

Stepien KM, Pastores GM, Hendroff U, McCormick C, Fitzimons P, Khawaja N, Borovickova I, Treacy EP.

JIMD Rep. 2018;41:29-36. doi: 10.1007/8904_2017_81. Epub 2018 Jan 3.

PubMed [citation]

PMID:: 29292490
PMCID:: PMC6122047

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004631096.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly185 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24332224, 29292490, 29665094). 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 GCDH protein function. This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 31737040, 34306040). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 185 of the GCDH protein (p.Gly185Glu).

#	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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