chr19-12896249-G-C

Variant names:

• chr19-12896249-G-C
• rs121434373
• NM_000159.4:c.680G>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM5 PP3 PP5_Very_Strong

The NM_000159.4(GCDH):​c.680G>C​(p.Arg227Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000394 in 1,612,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R227L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 1.81
• Publications: 31 publications found

Genes affected

GCDH (HGNC:4189): (glutaryl-CoA dehydrogenase) The protein encoded by this gene belongs to the acyl-CoA dehydrogenase family. It catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. The enzyme exists in the mitochondrial matrix as a homotetramer of 45-kD subunits. Mutations in this gene result in the metabolic disorder glutaric aciduria type 1, which is also known as glutaric acidemia type I. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 12. [provided by RefSeq, Mar 2013]

GCDH Gene-Disease associations (from GenCC):

• glutaryl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, Myriad Women’s Health

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000159.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-12896249-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1498017.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799
• PP5: Variant 19-12896249-G-C is Pathogenic according to our data. Variant chr19-12896249-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000159.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCDH	NM_000159.4	MANE Select	c.680G>C	p.Arg227Pro	missense	Exon 8 of 12	NP_000150.1
	GCDH	NM_013976.5		c.680G>C	p.Arg227Pro	missense	Exon 8 of 12	NP_039663.1
	GCDH	NR_102316.1		n.843G>C		non_coding_transcript_exon	Exon 8 of 12

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCDH	ENST00000222214.10	TSL:1 MANE Select	c.680G>C	p.Arg227Pro	missense	Exon 8 of 12	ENSP00000222214.4
	GCDH	ENST00000591470.5	TSL:1	c.680G>C	p.Arg227Pro	missense	Exon 7 of 11	ENSP00000466845.1
	GCDH	ENST00000714069.1		c.680G>C	p.Arg227Pro	missense	Exon 8 of 13	ENSP00000519360.1

Frequencies

GnomAD3 genomes AF: 0.000246 AC: 37 AN: 150460 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000445

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000183 AC: 46 AN: 251378 AF XY: 0.000221

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000410 AC: 599 AN: 1461772 Hom.: 0 Cov.: 33 AF XY: 0.000422 AC XY: 307 AN XY: 727184

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.000134 AC: 6 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000508 AC: 565 AN: 1111954

Other (OTH) AF: 0.000431 AC: 26 AN: 60394

GnomAD4 genome AF: 0.000246 AC: 37 AN: 150460 Hom.: 0 Cov.: 31 AF XY: 0.000191 AC XY: 14 AN XY: 73476

African (AFR) AF: 0.000147 AC: 6 AN: 40778

American (AMR) AF: 0.0000661 AC: 1 AN: 15140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.00 AC: 0 AN: 4748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000445 AC: 30 AN: 67394

Other (OTH) AF: 0.00 AC: 0 AN: 2062

Alfa AF: 0.0000878 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:9 Other:1

Jan 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Low-excreter; 85%-10% residual activity

Aug 02, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GCDH c.680G>C (p.Arg227Pro) variant, located in the beta-sandwich in close proximity to FAD, involves the alteration of a non-conserved nucleotide and 4/5 in silico tools predict a damaging outcome. A functional study, Biery_1996, supports these predictions with the observed significant decrease in GCDH activity. This variant was found in 21/121390 control chromosomes at a frequency of 0.000173, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355). Multiple publications have reported this variant in affected individuals presenting with mild to severe phenotypes, including two affected siblings. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic/pathogenic." Taken together, this variant is classified as pathogenic.

Nov 29, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GCDH c.680G>C (p.Arg227Pro) variant has been identified in at least 20 individuals with glutaric acidemia, including in a homozygous state in two individuals and in a compound heterozygous state in 18 individuals (Biery et al. 1996; Christensen et al. 1997; Busquets et al. 2000a; Busquets et al. 2000b; Zschocke et al. 2000; Bijarnia et al. 2008; Flamand-Rouviere et al. 2010; Couce et al. 2013). The p.Arg227Pro variant was absent from 400 controls but is reported at a frequency of 0.00026 in the Latino population of the Exome Aggregation Consortium. Functional studies demonstrated that p.Arg227Pro variant is associated with low residual activity of glutaryl-CoA dehydrogenase (GCDH) compared to wildtype (Biery et al. 1996; Christensen et al. 1997; Liesert et al. 1999; Bijarnia et al. 2008; Flamand-Rouviere et al. 2010). Additionally, the p.Arg227Pro variant was associated with atypical excretion of glutarate and 3-hydroxygluaratein urine analysis (Busquet et al. 2000a; Busquet et al. 2000b; Zschocke et al. 2000; Couce et al. 2013). Based on the collective evidence, the p.Arg227Pro variant is classified as pathogenic for glutaric acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000159.2(GCDH):c.680G>C(R227P) is classified as pathogenic in the context of glutaric acidemia, GCDH-related. Sources cited for classification include the following: PMID 8900227, 10960496, 10384381, 29665094, 11015709, 22728054, 30570710, 12872844 and 9266361. Classification of NM_000159.2(GCDH):c.680G>C(R227P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 227 of the GCDH protein (p.Arg227Pro). This variant is present in population databases (rs121434373, gnomAD 0.04%). This missense change has been observed in individual(s) with glutaric acidemia (PMID: 9266361, 10066389, 10960496, 11073722, 22728054, 23395213, 28438223). ClinVar contains an entry for this variant (Variation ID: 2089). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GCDH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCDH function (PMID: 8900227). For these reasons, this variant has been classified as Pathogenic.

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Oct 27, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 25, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:3

Sep 07, 2012

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 06, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a reduction in glutaryl-CoA dehydrogenase enzyme activity by more than 95% (Biery et al., 1996); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11073722, 9600243, 15505393, 28794906, 22728054, 25087612, 10699052, 10960496, 8900227, 28062662, 28438223, 10066389, 9266361, 10384381, 27397597, 18683078, 20629163, 23395213, 29458885, 30570710, 31491587, 12872844, 31589614)

Mar 06, 2019

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the GCDH gene demonstrated a sequence change, c.680G>C, in exon 8 that results in an amino acid change, p.Arg227Pro. This sequence change has been previously described in patients with glutaryl-CoA dehydrogenase (GCDH) deficiency in the homozygous and the compound heterozygous state (PMIDs: 10066389, 23395213, 9266361). This variant also showed reduced GCD activity by >95% when expressed in E coli (PMID: 8900227). This sequence change has been described in the gnomAD database with a low population frequency of 0.019% (dbSNP rs121434373). The p.Arg227Pro change affects a moderately conserved amino acid residue located in a domain of the GCDH protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg227Pro substitution.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		1.8
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.011	B
Vest4		0.66
MVP		0.87
MPC		0.52
ClinPred		0.20	T
GERP RS		0.23
Varity_R		0.97
gMVP		0.96
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121434373; hg19: chr19-13007063; COSMIC: COSV53369235; COSMIC: COSV53369235;