rs147611168
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_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
Consequence
NM_000159.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
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: 19AN: 152106Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000440 AC: 11AN: 250166Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135452
GnomAD4 exome AF: 0.0000773 AC: 113AN: 1461232Hom.: 0 Cov.: 32 AF XY: 0.0000784 AC XY: 57AN XY: 726964
GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152106Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13AN XY: 74306
ClinVar
Submissions by phenotype
Glutaric aciduria, type 1 Pathogenic:6Other: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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at