rs141437721

Variant names:

• chr19-12897833-A-G
• rs141437721
• NM_000159.4:c.1213A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PM1 PM5 PP5_Very_Strong BP4

The NM_000159.4(GCDH):​c.1213A>G​(p.Met405Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M405T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 2.56
• Publications: 15 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 11 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000159.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-12897834-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1995265.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 19-12897833-A-G is Pathogenic according to our data. Variant chr19-12897833-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 193798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38632983). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCDH	NM_000159.4	c.1213A>G	p.Met405Val	missense_variant	Exon 11 of 12	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5	c.1213A>G	p.Met405Val	missense_variant	Exon 11 of 12		NP_039663.1
GCDH	NR_102316.1	n.1376A>G		non_coding_transcript_exon_variant	Exon 11 of 12
GCDH	NR_102317.1	n.1594A>G		non_coding_transcript_exon_variant	Exon 10 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10	c.1213A>G	p.Met405Val	missense_variant	Exon 11 of 12	1	NM_000159.4	ENSP00000222214.4

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152038 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251232 AF XY: 0.0000442

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000472 AC: 69 AN: 1461800 Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28 AN XY: 727216

African (AFR) AF: 0.000836 AC: 28 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111972

Other (OTH) AF: 0.000149 AC: 9 AN: 60396

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152156 Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10 AN XY: 74376

African (AFR) AF: 0.000530 AC: 22 AN: 41522

American (AMR) AF: 0.000262 AC: 4 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000476 Hom.: 0

Bravo AF: 0.000280

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Pathogenic/Likely 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

Jun 01, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 19, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 04, 2018

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 405 of the GCDH protein (p.Met405Val). This variant is present in population databases (rs141437721, gnomAD 0.05%). This missense change has been observed in individual(s) with glutaric acidemia, type I (PMID: 17188916, 27397597, 28438223). ClinVar contains an entry for this variant (Variation ID: 193798). 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 not expected to disrupt GCDH protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Dec 28, 2023

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 13, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GCDH c.1213A>G (p.Met405Val) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251442 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GCDH causing Glutaric Acidemia Type 1 (6e-05 vs 0.0035), allowing no conclusion about variant significance. c.1213A>G has been reported in the literature (in compound heterozygous and homozygous state) in multiple individuals affected with Glutaric Acidemia Type 1 (GA-I) (e.g. Boy_2017, Cerisola_2009, Gallagher_2005, Korman_2007, Schillaci_2016). These data indicate that the variant is very likely to be associated with disease. These reports also indicated that this variant is associated with a low excretor biochemical phenotype, and therefore could potentially be missed by current new born screening programs that are using biochemical diagnosis based on elevated metabolites in the urine or blood (Schillaci_2016). The following publications have been ascertained in the context of this evaluation (PMID: 28438223, 19433275, 19167251, 16183314, 17188916, 27397597). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

common variant among low-excreter African Americans

Nov 08, 2021

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000159.2(GCDH):c.1213A>G(M405V) is a missense variant classified as pathogenic in the context of glutaric acidemia, GCDH-related. M405V has been observed in cases with relevant disease (PMID: 25590979, 19433275, 17188916, 27397597). Functional assessments of this variant are not available in the literature. M405V has been observed in population frequency databases (gnomAD: AFR 0.06%). In summary, NM_000159.2(GCDH):c.1213A>G(M405V) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 19, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.006%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.61 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.76 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000193798 /PMID: 17188916 /3billion dataset). A different missense change at the same codon (p.Met405Thr) has been reported to be associated with GCDH-related disorder (ClinVar ID: VCV001995265). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

not provided Pathogenic:2

Mar 19, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 01, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 16183314, 27397597, 25255367, 17188916, 28389991, 36976725, 28438223, 25590979, 36906724, 34207159, 34258142, 38296580, 37020324, 40517577, 40361251)

GCDH-related disorder Pathogenic:1

Nov 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GCDH c.1213A>G variant is predicted to result in the amino acid substitution p.Met405Val. This variant has been reported along with a second GCDH variant in patients with clinical and/or biochemical features of glutaric acidemia type I (for example, see Korman et al. 2007. PubMed ID: 17188916; Schillaci et al. 2016. PubMed ID: 27397597; Boy et al. 2017. PubMed ID: 28438223; Guenzal et al. 2021. PubMed ID: 34258142). It has been reported in association with reduced GCDH enzyme activity and low excretion of glutaric acid. Importantly, low-excretor patients may be more difficult to detect with biochemical testing as well as in newborn screening based on C5DC acylcarnitine (Schillaci et al. 2016. PubMed ID: 27397597; Larson et al. 2019. PubMed ID: 31536184). This variant is reported in 0.064% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-13008647-A-G). This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	21
DANN	Benign	0.76
DEOGEN2	Pathogenic	0.86	D;D
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.0	.;D
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Uncertain	-0.015	T
MutationAssessor	Benign	1.1	L;L
PhyloP100		2.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.1	N;.
REVEL	Uncertain	0.61
Sift	Benign	0.70	T;.
Sift4G	Benign	0.58	T;T
Vest4		0.80
ClinPred		0.68	D
GERP RS		4.7
PromoterAI		-0.074	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.96
Mutation Taster		=7/93	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: rs141437721; hg19: chr19-13008647;