chr19-12897735-G-A

Position:

• chr19-12897735-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The ENST00000222214.10(GCDH):​c.1115G>A​(p.Arg372Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,884 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R372G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GCDH ENST00000222214.10 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.80

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 11 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000222214.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-12897736-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2024012.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 19-12897735-G-A is Pathogenic according to our data. Variant chr19-12897735-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 557606.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}. Variant chr19-12897735-G-A is described in Lovd as [Pathogenic]. Variant chr19-12897735-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCDH	NM_000159.4	c.1115G>A	p.Arg372Lys	missense_variant	11/12	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5	c.1115G>A	p.Arg372Lys	missense_variant	11/12		NP_039663.1
GCDH	NR_102316.1	n.1278G>A		non_coding_transcript_exon_variant	11/12
GCDH	NR_102317.1	n.1496G>A		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10	c.1115G>A	p.Arg372Lys	missense_variant	11/12	1	NM_000159.4	ENSP00000222214	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 08, 2022	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 372 of the GCDH protein (p.Arg372Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glutaric acidemia type 1 (PMID: 10960496, 23395213). ClinVar contains an entry for this variant (Variation ID: 557606). 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. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 04, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.026	D;.
Sift4G	Benign	0.066	T;T
Polyphen		0.94	P;P
Vest4		0.77
MutPred		0.90		Gain of ubiquitination at R372 (P = 0.0592);Gain of ubiquitination at R372 (P = 0.0592);
MVP		0.98
MPC		1.1
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555751240; hg19: chr19-13008549;