rs147611168

Positions:

• chr19-12897860-G-A
• chr19-12897860-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000159.4(GCDH):​c.1240G>A​(p.Glu414Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,613,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. E414A) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 7.75

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 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 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 chr19-12897861-A-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 19-12897860-G-A is Pathogenic according to our data. Variant chr19-12897860-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 167133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12897860-G-A is described in Lovd as [Pathogenic]. Variant chr19-12897860-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCDH	NM_000159.4	c.1240G>A	p.Glu414Lys	missense_variant	11/12	ENST00000222214.10
GCDH	NM_013976.5	c.1240G>A	p.Glu414Lys	missense_variant	11/12
GCDH	NR_102316.1	n.1403G>A		non_coding_transcript_exon_variant	11/12
GCDH	NR_102317.1	n.1621G>A		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.1240G>A	p.Glu414Lys	missense_variant	11/12	1	NM_000159.4	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000735

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000440 AC: 11 AN: 250166 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135452

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.0000289

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: 0.0000621

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000773 AC: 113 AN: 1461232 Hom.: 0 Cov.: 32 AF XY: 0.0000784 AC XY: 57 AN XY: 726964

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000864

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152106 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74306

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000248 Hom.: 0

Bravo AF: 0.000113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 03, 2023	Variant summary: GCDH c.1240G>A (p.Glu414Lys) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250166 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GCDH causing Glutaric Acidemia Type 1 (4.4e-05 vs 0.0035), allowing no conclusion about variant significance. c.1240G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Glutaric Acidemia Type 1, including individuals of Lumbee heritage, a community in which it has been described as a founder variant (e.g. Basinger_2006, Boy_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in vitro (Keyser_2008) and found that variant effect results in <10% activity compared to the WT protein. The following publications have been ascertained in the context of this evaluation (PMID: 16466958, 28438223, 18775954). Seven 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 20, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	Founder variant in Lumbee Native Americans of North Carolina -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 414 of the GCDH protein (p.Glu414Lys). This variant is present in population databases (rs147611168, gnomAD 0.01%). This missense change has been observed in individual(s) with glutaric acidemia type I and has been described as a common cause of the disease in the Lumbee population (PMID: 8900227, 16466958, 19433437). It is commonly reported in individuals of Lumbee ancestry (PMID: 8900227, 16466958, 19433437). ClinVar contains an entry for this variant (Variation ID: 167133). 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%. Experimental studies have shown that this missense change affects GCDH function (PMID: 18775954). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jun 21, 2022	This variant has been reported in the literature in several individuals with glutaric aciduria type 1 in both the homozygous and compound heterozygous states (Biery 1996 PMID: 8900227; Basinger 2006 PMID: 16466958; Keyser 2008 PMID: 18775954; Harting 2009 PMID: 19433437; Boy 2017 PMID: 28438223; Peng 2018 PMID: 29458885; Xiao 2020 PMID: 32508882). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.02% [11/41408], (https://gnomad.broadinstitute.org/variant/19-12897860-G-A?dataset=gnomad_r3). Please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID: 167133). Evolutionary conservation and computational predictive tools support that this variant will impact the protein. In vitro functional studies also support that this variant will impact the protein, resulting in no enzymatic activity (Biery 1996 PMID: 8900227; Keyser 2008 PMID: 18775954). In summary, this variant is classified as pathogenic based on the data above. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2020	Published functional studies demonstrate that E414K had significantly reduced enzymatic activity when compared to wild-type (Keyser et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16466958, 28438223, 29201125, 25087612, 18775954, 8900227, 29458885, 19433437, 32508882, 31589614) -

GCDH-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 30, 2023

The GCDH c.1240G>A variant is predicted to result in the amino acid substitution p.Glu414Lys. This variant has been reported in the heterozygous state with a second GCDH variant in patients with glutaric acidemia type I (GA1) (Harting et al. 2009. PubMed ID: 19433437; Boy et al. 2017. PubMed ID: 28438223). The c.1240G>A variant has also been reported as a common pathogenic variant in the Lumbee population of North Carolina (Basinger et al. 2006. PubMed ID: 16466958). Internally, we have observed this variant in the homozygous state or compound heterozygous with a second causative GCDH variant in several individuals with abnormal newborn screens and follow-up biochemical testing suggestive of GA1. In functional studies, the p.Glu414Lys substitution, as well as a p.Glu414Gln mutation of the same codon, has been reported to lead to greatly reduced to absent enzyme activity (Biery et al. 1996. PubMed ID: 8900227; Keyser et al. 2008. PubMed ID: 18775954). The p.Glu414 amino acid residue is located in the enzyme active site, and the p.Glu414Lys substitution was noted to interfere with ligand binding in functional assays (Keyser et al. 2008. PubMed ID: 18775954). This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-13008674-G-A). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.1	H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.8	D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.75
MVP		0.99
MPC		1.2
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.99
gMVP		1.0

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: rs147611168; hg19: chr19-13008674;