chr19-12899522-C-T

Position:

• chr19-12899522-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000159.4(GCDH):​c.1298C>T​(p.Ala433Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,018 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A433E) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 7.58

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]

SYCE2 (HGNC:27411): (synaptonemal complex central element protein 2) The protein encoded by this gene is part of the synaptonemal complex formed between homologous chromosomes during meiotic prophase. The encoded protein associates with SYCP1 and SYCE1 and is found only where chromosome cores are synapsed. [provided by RefSeq, Dec 2012]

GCDH (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-12899522-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868
• PP5: Variant 19-12899522-C-T is Pathogenic according to our data. Variant chr19-12899522-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12899522-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCDH	NM_000159.4	c.1298C>T	p.Ala433Val	missense_variant	12/12	ENST00000222214.10	NP_000150.1
SYCE2	NM_001105578.2	c.613-137G>A		intron_variant		ENST00000293695.8	NP_001099048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10	c.1298C>T	p.Ala433Val	missense_variant	12/12	1	NM_000159.4	ENSP00000222214.4
SYCE2	ENST00000293695.8	c.613-137G>A		intron_variant		1	NM_001105578.2	ENSP00000293695.6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152190 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251312 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461828 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727228

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152190 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:4 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 19, 2023	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 433 of the GCDH protein (p.Ala433Val). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 10960496, 21176883, 29201125, 31952437). ClinVar contains an entry for this variant (Variation ID: 556228). 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 95%. Experimental studies have shown that this missense change affects GCDH function (PMID: 12948740). This variant disrupts the p.Ala433 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9600243). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, flagged submission	clinical testing	Counsyl	Jan 19, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 10, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 27, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.6	D;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.97	D;D
Vest4		0.18
MutPred		0.93		Gain of methylation at K438 (P = 0.0519);Gain of methylation at K438 (P = 0.0519);
MVP		0.99
MPC		0.56
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.80
gMVP		0.98

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: rs933624223; hg19: chr19-13010336;