19-12893485-T-C

Position:

• chr19-12893485-T-C

Variant summary

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

The ENST00000222214.10(GCDH):​c.337T>C​(p.Tyr113His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. Y113C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GCDH ENST00000222214.10 missense, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.72

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr19-12893486-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1469596.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 19-12893485-T-C is Pathogenic according to our data. Variant chr19-12893485-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12893485-T-C is described in Lovd as [Pathogenic]. Variant chr19-12893485-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCDH	NM_000159.4	c.337T>C	p.Tyr113His	missense_variant, splice_region_variant	6/12	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5	c.337T>C	p.Tyr113His	missense_variant, splice_region_variant	6/12		NP_039663.1
GCDH	NR_102316.1	n.500T>C		splice_region_variant, non_coding_transcript_exon_variant	6/12
GCDH	NR_102317.1	n.753T>C		splice_region_variant, non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10	c.337T>C	p.Tyr113His	missense_variant, splice_region_variant	6/12	1	NM_000159.4	ENSP00000222214	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461538 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 14, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 28, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 113 of the GCDH protein (p.Tyr113His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glutaric aciduria (PMID: 10699052, 19433437). ClinVar contains an entry for this variant (Variation ID: 557526). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects GCDH function (PMID: 28062662). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	.;D;D;D;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	H;.;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.4	D;.;.;.;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.018	D;.;.;.;.
Sift4G	Uncertain	0.032	D;D;D;D;D
Polyphen		0.062	B;.;B;.;.
Vest4		0.69
MutPred		0.90		Gain of ubiquitination at K111 (P = 0.1204);.;Gain of ubiquitination at K111 (P = 0.1204);.;.;
MVP		0.97
MPC		0.61
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.89

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: rs1555749853; hg19: chr19-13004299;