NM_000159.4(GCDH):c.1213dup (p.Met405fs) AND Glutaric aciduria, type 1

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: May 13, 2023
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:: RCV001377591.10

Allele description [Variation Report for NM_000159.4(GCDH):c.1213dup (p.Met405fs)]

NM_000159.4(GCDH):c.1213dup (p.Met405fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

19p13.13

Genomic location:

Preferred name:

NM_000159.4(GCDH):c.1213dup (p.Met405fs)

HGVS:

NC_000019.10:g.12897833dup
NG_009292.1:g.11674dup
NG_033049.1:g.26440dup
NM_000159.4:c.1213dupMANE SELECT
NM_013976.5:c.1213dup
NP_000150.1:p.Met405fs
NP_039663.1:p.Met405fs
NC_000019.9:g.13008646_13008647insA
NC_000019.9:g.13008647dup
NR_102316.1:n.1376dup
NR_102317.1:n.1594dup

Protein change:

M405fs

Links:

dbSNP: rs1377352983

NCBI 1000 Genomes Browser:

rs1377352983

Molecular consequence:

NM_000159.4:c.1213dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_013976.5:c.1213dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_102316.1:n.1376dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_102317.1:n.1594dup - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001574961	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 28, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9600243, 10699052, 24973495, 28492532
SCV002086998	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Jun 29, 2020)	germline	clinical testing
SCV004199244	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 13, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001574961

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 28, 2020)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002086998

Natera, Inc.

no assertion criteria provided

Likely pathogenic
(Jun 29, 2020)

germline

clinical testing

SCV004199244

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 13, 2023)

unknown

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	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

The human glutaryl-CoA dehydrogenase gene: report of intronic sequences and of 13 novel mutations causing glutaric aciduria type I.

Schwartz M, Christensen E, Superti-Furga A, Brandt NJ.

Hum Genet. 1998 Apr;102(4):452-8.

PubMed [citation]

PMID:: 9600243

Mutation analysis in glutaric aciduria type I.

Zschocke J, Quak E, Guldberg P, Hoffmann GF.

J Med Genet. 2000 Mar;37(3):177-81.

PubMed [citation]

PMID:: 10699052
PMCID:: PMC1734541

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001574961.4

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

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.Thr429 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9600243, 10699052, 24973495). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has not been reported in the literature in individuals with GCDH-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the GCDH gene (p.Met405Asnfs*14). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acids of the GCDH protein.

#	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., SCV002086998.1

#	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 Baylor Genetics, SCV004199244.1

#	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

Last Updated: Sep 29, 2024

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