NM_000159.4(GCDH):c.442G>A (p.Val148Ile) AND Glutaric aciduria, type 1

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 31, 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:: RCV003050529.6

Allele description [Variation Report for NM_000159.4(GCDH):c.442G>A (p.Val148Ile)]

NM_000159.4(GCDH):c.442G>A (p.Val148Ile)

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.442G>A (p.Val148Ile)

HGVS:

NC_000019.10:g.12893590G>A
NG_009292.1:g.7431G>A
NM_000159.3:c.442G>A
NM_000159.4:c.442G>AMANE SELECT
NM_013976.5:c.442G>A
NP_000150.1:p.Val148Ile
NP_039663.1:p.Val148Ile
NC_000019.9:g.13004404G>A
NM_000159.4:c.442G>A
NR_102316.1:n.605G>A
NR_102317.1:n.858G>A

Protein change:

V148I

Molecular consequence:

NM_000159.4:c.442G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_013976.5:c.442G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_102316.1:n.605G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_102317.1:n.858G>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003443120	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 31, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9600243, 24332224, 28492532
SCV004039399	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 25, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15505393, 24332224, 9600243, 16641220 Citation Link,
SCV004191001	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 13, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005367967	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	no assertion criteria provided (ACMG Guidelines, 2015)	Likely pathogenic (Aug 7, 2024)	paternal	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	paternal	yes	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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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 (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443120.2

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

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 148 of the GCDH protein (p.Val148Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 9600243, 24332224). ClinVar contains an entry for this variant (Variation ID: 2138244). 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%. 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004039399.1

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

Description

Variant summary: GCDH c.442G>A (p.Val148Ile) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251470 control chromosomes (gnomAD). c.442G>A has been reported in the literature in multiple bi-allelic individuals affected with Glutaric Acidemia Type 1 (examples: Schwartz_1998, Kolker_2006, Christensen_2004, and Wang_2014). These data indicate that the variant is very likely to be associated with disease. Multiple publications have reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (examples: Schwartz_1998, Kolker_2006, Christensen_2004). The following publications have been ascertained in the context of this evaluation (PMID: 9600243, 16641220, 15505393, 24332224). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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 Baylor Genetics, SCV004191001.1

#	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 Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals, SCV005367967.1

#	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	paternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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