NM_000159.4(GCDH):c.1207C>T (p.His403Tyr) AND Glutaric aciduria, type 1

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: May 17, 2022
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:: RCV000852302.4

Allele description [Variation Report for NM_000159.4(GCDH):c.1207C>T (p.His403Tyr)]

NM_000159.4(GCDH):c.1207C>T (p.His403Tyr)

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.1207C>T (p.His403Tyr)

HGVS:

NC_000019.10:g.12897827C>T
NG_009292.1:g.11668C>T
NG_033049.1:g.26446G>A
NM_000159.4:c.1207C>TMANE SELECT
NM_013976.5:c.1207C>T
NP_000150.1:p.His403Tyr
NP_039663.1:p.His403Tyr
NC_000019.9:g.13008641C>T
NC_000019.9:g.13008641C>T
NR_102316.1:n.1370C>T
NR_102317.1:n.1588C>T
p.His403Tyr

Protein change:

H403Y

Links:

dbSNP: rs1599619080

NCBI 1000 Genomes Browser:

rs1599619080

Molecular consequence:

NM_000159.4:c.1207C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_013976.5:c.1207C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_102316.1:n.1370C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_102317.1:n.1588C>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
SCV000928319	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 30, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003443131	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 17, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24332224, 34504725, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000928319

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 30, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003443131

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 17, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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
Indian Hindu	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Clinical and mutational spectra of 23 Chinese patients with glutaric aciduria type 1.

Wang Q, Li X, Ding Y, Liu Y, Song J, Yang Y.

Brain Dev. 2014 Oct;36(9):813-22. doi: 10.1016/j.braindev.2013.11.006. Epub 2013 Dec 9.

PubMed [citation]

PMID:: 24332224

See all PubMed Citations (4)

Details of each submission

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV000928319.1

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

Description

Homozygous variant c.1207C>T (p.His403Tyr) in exon 11 has been observed in GCDH gene. The proband born to non-consanguineous parents, presented with clinical indications of inability to hold neck. The patient was found to be homozygous and parents were heterozygous carriers for thee said variant. The variant has not been reported in the 1000 genomes and ExAC, dbSNP or any other databases. The in-silico prediction of the variant is possibly damaging by MutationTaster2, Polyphen2, Provean and FATHMM softwares. In summary, the said variant meets our criteria to be classified as likely pathogenic based on the mode of inheritance, in silico prediction and allele frequency in population databases.

#	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		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443131.2

#	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 histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 403 of the GCDH protein (p.His403Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Glutaric acidemia, type I (PMID: 24332224, 34504725). ClinVar contains an entry for this variant (Variation ID: 691529). 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. 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

Last Updated: Sep 29, 2024

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