rs141437721

chr19-12897833-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1 PM2 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:10 O:1
• Conservation: PhyloP100: 2.56

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]

ACMG classification

Verdict is Pathogenic. Variant got 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, 2 uncertain in NM_000159.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-12897834-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id 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 [Likely_pathogenic]. Clinvar id is 193798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12897833-A-G is described in Lovd as [Pathogenic]. Variant chr19-12897833-A-G is described in Lovd as [Pathogenic]. Variant chr19-12897833-A-G is described in Lovd as [Likely_pathogenic].
• 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/exons	MANE	UniProt
GCDH	NM_000159.4	c.1213A>G	p.Met405Val	missense_variant	11/12	ENST00000222214.10
GCDH	NM_013976.5	c.1213A>G	p.Met405Val	missense_variant	11/12
GCDH	NR_102316.1	n.1376A>G		non_coding_transcript_exon_variant	11/12
GCDH	NR_102317.1	n.1594A>G		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.1213A>G	p.Met405Val	missense_variant	11/12	1	NM_000159.4	P1

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

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251232 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135848

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 SAS 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

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.000149

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

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000225 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:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:7 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jul 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 13, 2023	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. -
not provided, no classification provided	literature only	GeneReviews	-	common variant among low-excreter African Americans -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 08, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2018	The M405V variant in the GCDH gene has previously been reported in several unrelated individuals with GA1 (Korman et al., 2007; Bhattacharjee et al., 2014; Schillaci et al., 2016). This variant has been associated with low excretion of glutaric acid in urine and may be missed by various newborn screening programs (Schillaci et al., 2016). In summary, we interpret M405V to be a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 19, 2015	- -

GCDH-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2023

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
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Uncertain	-0.015	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	D;D;D;D
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
Polyphen		0.0080	B;B
Vest4		0.80
MVP		0.95
MPC		0.65
ClinPred		0.68	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs141437721; hg19: chr19-13008647;