NM_000159.4(GCDH):c.1244-2A>C AND Glutaric aciduria, type 1

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Mar 5, 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:: RCV000174223.24

Allele description [Variation Report for NM_000159.4(GCDH):c.1244-2A>C]

NM_000159.4(GCDH):c.1244-2A>C

Genes:

LOC126862860:BRD4-independent group 4 enhancer GRCh37_chr19:13010146-13011345 [Gene]
GCDH:glutaryl-CoA dehydrogenase [Gene - OMIM - HGNC]
SYCE2:synaptonemal complex central element protein 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.13

Genomic location:

Preferred name:

NM_000159.4(GCDH):c.1244-2A>C

HGVS:

NC_000019.10:g.12899466A>C
NG_009292.1:g.13307A>C
NG_033049.1:g.24807T>G
NG_087357.1:g.235A>C
NM_000159.4:c.1244-2A>CMANE SELECT
NM_001105578.2:c.613-81T>GMANE SELECT
NM_013976.5:c.1244-234A>C
NC_000019.9:g.13010280A>C
NM_000159.2:c.1244-2A>C
NM_000159.3:c.1244-2A>C

Links:

dbSNP: rs199999619

NCBI 1000 Genomes Browser:

rs199999619

Molecular consequence:

NM_001105578.2:c.613-81T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_013976.5:c.1244-234A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000159.4:c.1244-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV000695715	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 25, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15505393, 18683078, 11058907 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000853109	SingHealth Duke-NUS Institute of Precision Medicine	no assertion criteria provided	Pathogenic (Jun 7, 2017)	germline	curation
SCV000893505	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 18, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000940791	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 13, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11058907, 15505393, 25256449, 27672653, 17576681, 9536098, 28492532
SCV001456400	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002024221	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 17, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002060356	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Pathogenic (Oct 1, 2021)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11058907, 23104440 Citation Link,
SCV004198742	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 5, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005417388	Juno Genomics, Hangzhou Juno Genomics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	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	no	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	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

Citations

PubMed

Glutaric aciduria type I: outcome following detection by newborn screening.

Bijarnia S, Wiley V, Carpenter K, Christodoulou J, Ellaway CJ, Wilcken B.

J Inherit Metab Dis. 2008 Aug;31(4):503-7. doi: 10.1007/s10545-008-0912-z. Epub 2008 Aug 9.

PubMed [citation]

PMID:: 18683078

Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency.

Christensen E, Ribes A, Merinero B, Zschocke J.

J Inherit Metab Dis. 2004;27(6):861-8.

PubMed [citation]

PMID:: 15505393

See all PubMed Citations (10)

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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695715.1

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

Description

Variant summary: The GCDH c.1244-2A>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splicing algorithms predict this variant to abolish the splice acceptor site. This variant was found in 10/121612 control chromosomes at a frequency of 0.0000822, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355).However, the variant was identified in multiple GA-1 patients in compound heterozygous or homozygous state and was shown to segregate with disease in at least one family. In addition, one clinical diagnostic laboratory 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 SingHealth Duke-NUS Institute of Precision Medicine, SCV000853109.1

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

#	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

From Fulgent Genetics, Fulgent Genetics, SCV000893505.2

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000940791.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change affects an acceptor splice site in intron 11 of the GCDH gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs199999619, gnomAD 0.1%). Disruption of this splice site has been observed in individual(s) with glutaric aciduria, type I (PMID: 11058907, 15505393, 25256449, 27672653). 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. This variant is also known as IVS10-2A>C. ClinVar contains an entry for this variant (Variation ID: 193976). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 Natera, Inc., SCV001456400.1

#	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, SCV002024221.3

#	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 Myriad Genetics, Inc., SCV002060356.2

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

Description

NM_000159.2(GCDH):c.1244-2A>C is a canonical splice variant classified as pathogenic in the context of glutaric acidemia, GCDH-related. c.1244-2A>C has been observed in cases with relevant disease (PMID: 23104440, 11058907). Functional assessments of this variant are not available in the literature. c.1244-2A>C has been observed in population frequency databases (gnomAD: EAS 0.12%). In summary, NM_000159.2(GCDH):c.1244-2A>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. 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 Baylor Genetics, SCV004198742.2

#	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 Juno Genomics, Hangzhou Juno Genomics, Inc, SCV005417388.1

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

Description

PM2_Supporting+PVS1_Strong+PM3_VeryStrong+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

Last Updated: Nov 30, 2024

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