NM_000159.4(GCDH):c.764C>T (p.Ser255Leu) AND Glutaric aciduria, type 1

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Jul 23, 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:: RCV000674290.15

Allele description [Variation Report for NM_000159.4(GCDH):c.764C>T (p.Ser255Leu)]

NM_000159.4(GCDH):c.764C>T (p.Ser255Leu)

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.764C>T (p.Ser255Leu)

HGVS:

NC_000019.10:g.12896333C>T
NG_009292.1:g.10174C>T
NM_000159.4:c.764C>TMANE SELECT
NM_013976.5:c.764C>T
NP_000150.1:p.Ser255Leu
NP_039663.1:p.Ser255Leu
NC_000019.9:g.13007147C>T
NM_000159.2:c.764C>T
NM_000159.3:c.764C>T
NR_102316.1:n.927C>T
NR_102317.1:n.1145C>T

Protein change:

S255L

Links:

dbSNP: rs758503371

NCBI 1000 Genomes Browser:

rs758503371

Molecular consequence:

NM_000159.4:c.764C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_013976.5:c.764C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_102316.1:n.927C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_102317.1:n.1145C>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
SCV000799600	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Apr 26, 2018)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25204480, 19433275, 25762492, 27351573, 10960496 Citation Link,
SCV000894187	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000934730	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 3, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10960496, 25204480, 25762492, 27351573, 28492532
SCV002086976	Natera, Inc.	no assertion criteria provided	Pathogenic (Aug 19, 2020)	germline	clinical testing
SCV003807241	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 17, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004191003	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 10, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005202914	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 23, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25762492, 10960496, 27351573 Citation Link,
SCV005329643	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 20, 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	1	not provided	not provided	1	not provided	clinical testing
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

Seizures versus dystonia in encephalopathic crisis of glutaric aciduria type I.

Cerisola A, Campistol J, Pérez-Dueñas B, Poo P, Pineda M, García-Cazorla A, Sanmartí FX, Ribes A, Vilaseca MA.

Pediatr Neurol. 2009 Jun;40(6):426-31. doi: 10.1016/j.pediatrneurol.2008.12.009.

PubMed [citation]

PMID:: 19433275

Molecular determination of glutaric aciduria type I in individuals from southwest Iran.

Baradaran M, Galehdari H, Aminzadeh M, Azizi Malmiri R, Tangestani R, Karimi Z.

Arch Iran Med. 2014 Sep;17(9):629-32. doi: 0141709/AIM.009.

PubMed [citation]

PMID:: 25204480

See all PubMed Citations (7)

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 Counsyl, SCV000799600.1

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

#	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 Fulgent Genetics, Fulgent Genetics, SCV000894187.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000934730.4

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

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 255 of the GCDH protein (p.Ser255Leu). This variant is present in population databases (rs758503371, gnomAD 0.006%). This missense change has been observed in individual(s) with glutaryl-CoA dehydrogenase deficiency (PMID: 10960496, 25204480, 25762492, 27351573). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 374435). 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 Natera, Inc., SCV002086976.1

#	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 Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807241.1

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

Description

ACMG classification criteria: PS4 strong, PM2, PM3 strong, PM5 moderated, PP1 supporting, PP3 supporting, PP4

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

From Baylor Genetics, SCV004191003.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005202914.1

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

Description

Variant summary: GCDH c.764C>T (p.Ser255Leu) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251318 control chromosomes. c.764C>T has been reported in the literature in individuals affected with Glutaric Acidemia Type 1 (examples: Gupta_2015, Qian_2016, Busquets_2000). These data indicate that the variant is likely to be associated with disease. Different variant affecting this residue has been classified pathogenic in ClinVar (c.763T>C (p.Ser255Pro) ). The following publications have been ascertained in the context of this evaluation (PMID: 10960496, 27351573, 25762492). ClinVar contains an entry for this variant (Variation ID: 374435). 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 Neuberg Centre For Genomic Medicine, NCGM, SCV005329643.1

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

Description

The observed missense c.764C>T(p.Ser255Leu)variant in GCDH gene has been reported in homozygous or compound heterozygous state in individual(s) affected with Glutaric Acidemia (Qian GL, et. al., 2016; Gupta N, et. al., 2015; Busquets C, et. al., 2000). This variant has been reported to segregate with disease in affected individuals (Qian GL, et. al., 2016). This p.Ser255Leu variant is present with an allele frequency of 0.0008% in gnomAD Exomes database. This variant has been suported to the ClinVar database as Likely pathogenic/Pathogenic. Multiple lines of computational evidence (Polyphen - probably damaging , SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Ser255Leu in GCDH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 255 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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