NM_000159.4(GCDH):c.1198G>A (p.Val400Met) AND Glutaric aciduria, type 1

Germline classification:: Pathogenic (11 submissions)
Last evaluated:: Mar 30, 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:: RCV000002169.29

Allele description [Variation Report for NM_000159.4(GCDH):c.1198G>A (p.Val400Met)]

NM_000159.4(GCDH):c.1198G>A (p.Val400Met)

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.1198G>A (p.Val400Met)

HGVS:

NC_000019.10:g.12897818G>A
NG_009292.1:g.11659G>A
NG_033049.1:g.26455C>T
NM_000159.4:c.1198G>AMANE SELECT
NM_013976.5:c.1198G>A
NP_000150.1:p.Val400Met
NP_039663.1:p.Val400Met
NC_000019.9:g.13008632G>A
NM_000159.2:c.1198G>A
NM_000159.3:c.1198G>A
NR_102316.1:n.1361G>A
NR_102317.1:n.1579G>A
Q92947:p.Val400Met

Protein change:

V400M; VAL400MET

Links:

UniProtKB: Q92947#VAR_000411; OMIM: 608801.0008; dbSNP: rs121434372

NCBI 1000 Genomes Browser:

rs121434372

Molecular consequence:

NM_000159.4:c.1198G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_013976.5:c.1198G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_102316.1:n.1361G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_102317.1:n.1579G>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

Recent activity

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S41 family peptidase [Segatella hominis]
S41 family peptidase [Segatella hominis]
gi|2619009897|gnl|PRJNA684333|KUA50 65|gb|WOZ80954.1|

Protein
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znf234 zinc finger protein 234 [Xenopus tropicalis]
znf234 zinc finger protein 234 [Xenopus tropicalis]
Gene ID:100496886

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000022327	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 2012)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 8900227, 21912879
SCV000678044	Counsyl	no assertion criteria provided	Likely pathogenic (Feb 15, 2014)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9711871, 21912879, 15505393, 10960496, 8900227, 9881681
SCV000756246	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10960496, 21912879, 27397597, 28492532
SCV000893503	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 2, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000919422	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 26, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10960496, 15505393 Citation Link,
SCV001133277	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 9266361, 10960496, 31536184
SCV001140998	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001456397	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002024215	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 17, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004199197	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005051786	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID]

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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, literature only
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Glutaryl-CoA dehydrogenase mutations in glutaric acidemia (type I): review and report of thirty novel mutations.

Goodman SI, Stein DE, Schlesinger S, Christensen E, Schwartz M, Greenberg CR, Elpeleg ON.

Hum Mutat. 1998;12(3):141-4. Review.

PubMed [citation]

PMID:: 9711871

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

See all PubMed Citations (11)

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, SCV000022327.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In patients with glutaric acidemia I (GA1; 231670), Biery et al. (1996) identified homozygosity for a 1234G-A transition in the GCDH gene, resulting in a val400-to-met (V400M) substitution.

Marti-Masso et al. (2012) reported 2 adult Spanish sisters with onset in infancy of a severe progressive form of dystonia affecting the upper and lower limbs, face, neck, and trunk, and resulting in severe speech impairment and the inability to walk by the teenage years. Neither had macrocephaly, organomegaly, cognitive impairment, or acute encephalopathy in childhood. Whole-exome sequence analysis identified a homozygous V400M mutation, consistent with glutaric acidemia. Laboratory studies showed decreased long-chain acylcarnitines and high excretion of 3-hydroxyglutaric acid, but urinary glutaric acid excretion was normal. Brain imaging showed increased signals in the lenticular nuclei. The findings implicated mitochondrial fatty acid metabolism as an important pathway in the development of dystonia, and Marti-Masso et al. (2012) concluded that GCDH mutation analysis should be considered in the differential diagnosis of progressive forms of early-onset generalized dystonia.

#	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 Counsyl, SCV000678044.2

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000756246.8

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

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 400 of the GCDH protein (p.Val400Met). This variant is present in population databases (rs121434372, gnomAD 0.02%). This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 10960496, 21912879, 27397597). ClinVar contains an entry for this variant (Variation ID: 2088). 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 GCDH protein function with a negative predictive value of 80%. 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, SCV000893503.2

#	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	unknown	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, SCV000919422.1

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

Description

Variant summary: The GCDH c.1198G>A (p.Val400Met) variant involves the alteration of a conserved nucleotide that lies within the acyl-CoA dehydrogenase/oxidase C-terminal domain (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 28/277188 control chromosomes at a frequency of 0.000101, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355). The variant has been identified in numerous glutaric acidemia I patients in homozygosity and compound heterozygosity (Busquets_2000; Christensen_2004). Studies on the residual GCDH enzyme activity levels in these patients show a range from almost no activity when in compound heterozygosity with a known null mutation (e.g., R402W), up to 30% of normal activity when in compound heterozygosity with a mild mutation (e.g., R227P). In homozygosity, the GCDH activity levels were 5-15% of WT ( Busquets_2000 and CHRISTENSEN_2004). 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 GeneReviews, SCV001133277.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

common variant among low excreters in Spain

#	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 Mendelics, SCV001140998.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001456397.1

#	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, SCV002024215.3

#	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 Baylor Genetics, SCV004199197.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005051786.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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