NM_000159.4(GCDH):c.1204C>T (p.Arg402Trp) AND Glutaric aciduria, type 1

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (14 submissions)
Last evaluated:: Jan 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000002166.37

Allele description

NM_000159.4(GCDH):c.1204C>T (p.Arg402Trp)

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.1204C>T (p.Arg402Trp)

HGVS:

NC_000019.10:g.12897824C>T
NG_009292.1:g.11665C>T
NG_033049.1:g.26449G>A
NM_000159.4:c.1204C>TMANE SELECT
NM_013976.5:c.1204C>T
NP_000150.1:p.Arg402Trp
NP_039663.1:p.Arg402Trp
NC_000019.9:g.13008638C>T
NM_000159.2:c.1204C>T
NM_000159.3:c.1204C>T
NR_102316.1:n.1367C>T
NR_102317.1:n.1585C>T
Q92947:p.Arg402Trp

Protein change:

R402W; ARG402TRP

Links:

UniProtKB: Q92947#VAR_000412; OMIM: 608801.0004; dbSNP: rs121434369

NCBI 1000 Genomes Browser:

rs121434369

Molecular consequence:

NM_000159.4:c.1204C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_013976.5:c.1204C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_102316.1:n.1367C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_102317.1:n.1585C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000022324	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 2000)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000410870	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 27, 2017)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 25762492, 18775954, 9600243, 10649503, 10960496, 11073722, 25256449, 10699052, 8900227, 24973495 Citation Link,
SCV000695714	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 6, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8900227, 10699052, 25762492, 10649503, 18775954 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000756248	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 10649503, 11073722, 20732827, 28352331, 28438223, 8900227, 18775954, 28492532
SCV000893504	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000923436	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001133282	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (5) [See all records that cite these PMIDs] 9600243, 11073722, 25762492, 28794906, 31536184
SCV001163800	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001193812	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Likely pathogenic (Dec 4, 2019)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8900227, 10699052, 24973495, 18775954 Citation Link,
SCV001442996	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 1, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001478369	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 28, 2019)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002059416	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002086996	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 27, 2017)	germline	clinical testing
SCV003818113	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 6, 2023)	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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	2	1	not provided	3	yes	clinical testing

Citations

PubMed

Glutaryl-CoA dehydrogenase deficiency in Spain: evidence of two groups of patients, genetically, and biochemically distinct.

Busquets C, Merinero B, Christensen E, Gelpí JL, Campistol J, Pineda M, Fernández-Alvarez E, Prats JM, Sans A, Arteaga R, Martí M, Campos J, Martínez-Pardo M, Martínez-Bermejo A, Ruiz-Falcó ML, Vaquerizo J, Orozco M, Ugarte M, Coll MJ, Ribes A.

Pediatr Res. 2000 Sep;48(3):315-22.

PubMed [citation]

PMID:: 10960496

Rare Late-Onset Presentation of Glutaric Aciduria Type I in a 16-Year-Old Woman with a Novel GCDH Mutation.

Fraidakis MJ, Liadinioti C, Stefanis L, Dinopoulos A, Pons R, Papathanassiou M, Garcia-Villoria J, Ribes A.

JIMD Rep. 2015;18:85-92. doi: 10.1007/8904_2014_353. Epub 2014 Sep 26.

PubMed [citation]

PMID:: 25256449
PMCID:: PMC4361931

See all PubMed Citations (17)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From OMIM, SCV000022324.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a large study of 48 European patients with glutaric acidemia I (GA1; 231670), Zschocke et al. (2000) found that the most common GCDH mutation was a 1204C-T change, resulting in an arg402-to-trp (R402W) substitution; it was present in 14 of 36 alleles (40%) in patients of German origin.

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

From Illumina Laboratory Services, Illumina, SCV000410870.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The GCDH c.1204C>T (p.Arg402Trp) variant has been described in at least nine studies and is found in at least 63 individuals with glutaric acidemia, including 26 in a homozygous state, 18 in a compound heterozygous state, and nine in a heterozygous state (Biery et al. 1996; Schwartz et al. 1998; Busquets et al. 2000a; Busquets et al. 2000b; Busquets et al. 2000c; Zschocke et al. 2000; Fraidakis et al. 2014; Georgiou et al. 2014; Gupta et al. 2015). The variant is found in an additional 24 disease alleles of unknown zygosity (Biery et al. 1996; Zschocke et al. 2000). The p.Arg402Trp variant has been described as the most common variant in different populations being present in 10-20% of alleles in affected individuals (Zschocke et al. 2000; Fraidakis et al. 2014). The p.Arg402Trp variant was absent from 100 unrelated Spanish controls and is reported at a frequency of 0.00076 in the European (Finnish) population of the Exome Aggregation Consortium. Expression of the p.Arg402Trp variant in E.coli and cultured fibroblasts showed reduced GCD activity compared to wild type, with 3% and <1% residual activity, respectively (Biery et al. 1996; Busquets et al. 2000b; Schwartz et al. 1998). Keyser et al. (2008) also demonstrated a reduced enzyme activity for the variant of 1.6% of wild type in mammalian cells and an increased degradation of the protein compared to wild type. The Arg402 residue is highly conserved. Based on the collective evidence, the p.Arg402Trp variant is classified as pathogenic for glutaric acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695714.1

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

Description

Variant summary: The GCDH c.1204C>T (p.Arg402Trp) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 27/120918 control chromosomes at a frequency of 0.0002233, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355). The variant was found in multiple affected individuals with an established diagnosis of GA-I based on the clinical symptoms, characteristic findings on neuroimaging and quantitative analysis of organic acids in urine. Busquets (2000) and Zschocke (2000) report the frequency of the variant of interest in affected individuals as 22% and 25%, respectively. Functional studies using expression systems show the variant to have a complete loss of GCDH activity (Biery_1996, Keyser_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

#	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

From Invitae, SCV000756248.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 402 of the GCDH protein (p.Arg402Trp). This variant is present in population databases (rs121434369, gnomAD 0.07%). This missense change has been observed in individual(s) with glutaric acidemia I and is the most common cause of glutaric acidemia I in Europe (PMID: 8900227, 10649503, 11073722, 20732827, 28352331, 28438223). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2085). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCDH function (PMID: 8900227, 18775954). For these reasons, this variant has been classified as Pathogenic.

#	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

From Fulgent Genetics, Fulgent Genetics, SCV000893504.1

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

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

From Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV000923436.1

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

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

From GeneReviews, SCV001133282.2

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

Description

Most common pan ethnic pathogenic variant

#	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

From Baylor Genetics, SCV001163800.1

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

#	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

From Myriad Genetics, Inc., SCV001193812.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

NM_000159.2(GCDH):c.1204C>T(R402W) is classified as likely pathogenic in the context of GCDH-related glutaric acidemia. Sources cited for classification include the following: PMID 8900227, 10699052, 24973495 and 18775954. Classification of NM_000159.2(GCDH):c.1204C>T(R402W) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening.

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001442996.1

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

Description

PS3, PS4_Supporting, PM2, PM3_Strong, PP4

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

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV001478369.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	yes	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	3	not provided	discovery		2	not provided	1	not provided

From Centogene AG - the Rare Disease Company, SCV002059416.1

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

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

From Natera, Inc., SCV002086996.1

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

#	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

From Revvity Omics, Revvity, SCV003818113.2

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

#	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: Jun 9, 2024

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