19-12891311-C-CT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000159.4(GCDH):c.8dup(p.Arg4GlufsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L3L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCDH NM_000159.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.453

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 592 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-12891311-C-CT is Pathogenic according to our data. Variant chr19-12891311-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 1070084.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCDH	NM_000159.4	c.8dup	p.Arg4GlufsTer39	frameshift_variant	2/12	ENST00000222214.10
GCDH	NM_013976.5	c.8dup	p.Arg4GlufsTer39	frameshift_variant	2/12
GCDH	NR_102316.1	n.116dup		non_coding_transcript_exon_variant	2/12
GCDH	NR_102317.1	n.116dup		non_coding_transcript_exon_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.8dup	p.Arg4GlufsTer39	frameshift_variant	2/12	1	NM_000159.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 12, 2020

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in GCDH are known to be pathogenic (PMID: 10699052, 11854167, 16602100). This variant has not been reported in the literature in individuals with GCDH-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg4Glufs*39) in the GCDH gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-13002125;