19-12891305-A-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000159.4(GCDH):c.1A>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000165 in 1,453,548 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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: GCDH NM_000159.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.51

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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000159.4 (GCDH) was described as [Likely_pathogenic] in ClinVar as 551240
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-12891305-A-C is Pathogenic according to our data. Variant chr19-12891305-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCDH	NM_000159.4	c.1A>C	p.Met1?	start_lost	2/12	ENST00000222214.10
GCDH	NM_013976.5	c.1A>C	p.Met1?	start_lost	2/12
GCDH	NR_102316.1	n.109A>C		non_coding_transcript_exon_variant	2/12
GCDH	NR_102317.1	n.109A>C		non_coding_transcript_exon_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.1A>C	p.Met1?	start_lost	2/12	1	NM_000159.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1453548 Hom.: 0 Cov.: 34 AF XY: 0.0000152 AC XY: 11 AN XY: 723482

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: 0.0000216

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 20, 2022	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Trp50 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 552917). Disruption of the initiator codon has been observed in individual(s) with glutaric acidemia type I (PMID: 29665094). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the GCDH mRNA. The next in-frame methionine is located at codon 80. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 18, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Benign	23
Dann	Benign	0.90
DEOGEN2	Benign	0.40	T;.;T;T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-0.50	N;.;.;.;.
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;T;D
Polyphen		0.85	P;.;P;.;.
Vest4		0.80
MutPred		0.97		Gain of stability (P = 0.0591);Gain of stability (P = 0.0591);Gain of stability (P = 0.0591);Gain of stability (P = 0.0591);Gain of stability (P = 0.0591);
MVP		0.98
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.72

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: rs1197426645; hg19: chr19-13002119;