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NM_000159.4(GCDH):c.679C>G (p.Arg227Gly) AND Glutaric aciduria, type 1

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Mar 18, 2022
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:
RCV003031954.3

Allele description [Variation Report for NM_000159.4(GCDH):c.679C>G (p.Arg227Gly)]

NM_000159.4(GCDH):c.679C>G (p.Arg227Gly)

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.679C>G (p.Arg227Gly)
HGVS:
  • NC_000019.10:g.12896248C>G
  • NG_009292.1:g.10089C>G
  • NM_000159.4:c.679C>GMANE SELECT
  • NM_013976.5:c.679C>G
  • NP_000150.1:p.Arg227Gly
  • NP_039663.1:p.Arg227Gly
  • NC_000019.9:g.13007062C>G
  • NR_102316.1:n.842C>G
  • NR_102317.1:n.1060C>G
Protein change:
R227G
Molecular consequence:
  • NM_000159.4:c.679C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_013976.5:c.679C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_102316.1:n.842C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_102317.1:n.1060C>G - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV003330479Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Mar 18, 2022)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Gene structure and mutations of glutaryl-coenzyme A dehydrogenase: impaired association of enzyme subunits that is due to an A421V substitution causes glutaric acidemia type I in the Amish.

Biery BJ, Stein DE, Morton DH, Goodman SI.

Am J Hum Genet. 1996 Nov;59(5):1006-11.

PubMed [citation]
PMID:
8900227
PMCID:
PMC1914837

Compound heterozygosity in the glutaryl-CoA dehydrogenase gene with R227P mutation in one allele is associated with no or very low free glutarate excretion.

Christensen E, Ribes A, Busquets C, Pineda M, Duran M, Poll-The BT, Greenberg CR, Leffers H, Schwartz M.

J Inherit Metab Dis. 1997 Jul;20(3):383-6. No abstract available.

PubMed [citation]
PMID:
9266361
See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003330479.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg227 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8900227, 9266361, 10066389, 10960496, 11073722, 22728054, 23395213, 28438223). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 variant has not been reported in the literature in individuals affected with GCDH-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 227 of the GCDH protein (p.Arg227Gly).

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

Last Updated: Sep 29, 2024