19-12897786-TG-TGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000159.4(GCDH):c.1173dup(p.Asn392GlufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,764 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L389L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: GCDH NM_000159.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.579

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-12897786-T-TG is Pathogenic according to our data. Variant chr19-12897786-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555570.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.1173dup	p.Asn392GlufsTer5	frameshift_variant	11/12	ENST00000222214.10
GCDH	NM_013976.5	c.1173dup	p.Asn392GlufsTer5	frameshift_variant	11/12
GCDH	NR_102316.1	n.1336dup		non_coding_transcript_exon_variant	11/12
GCDH	NR_102317.1	n.1554dup		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.1173dup	p.Asn392GlufsTer5	frameshift_variant	11/12	1	NM_000159.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151518 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000589

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461246 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726984

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: 0.0000348

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151518 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73962

Gnomad4 AFR AF: 0.00

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: 0.0000589

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 29, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 27, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 11, 2023	This sequence change creates a premature translational stop signal (p.Asn392Glufs*5) in the GCDH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GCDH are known to be pathogenic (PMID: 10699052, 11854167, 16602100). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with glutaric acidemia (PMID: 25762492). ClinVar contains an entry for this variant (Variation ID: 555570). For these reasons, this variant has been classified as Pathogenic. -

GCDH-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2023

The GCDH c.1173dupG variant is predicted to result in a frameshift and premature protein termination (p.Asn392Glufs*5). This variant has been reported in individuals with glutaric acidemia 1, including in the homozygous state in three affected members of one family (Gupta et al. 2015. PubMed ID: 25762492; https://www.ejmanager.com/mnstemps/173/173-1495636462.pdf?t=1641228585). In addition, it has been reported along with a pathogenic GCDH variant in a study of individuals with motor, speech/language, cognitive, behavioral, or intellectual abnormalities (sample S0993 in Table S2, Dong et al. 2020. PubMed ID: 32005694). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-13008600-T-TG). Frameshift variants in GCDH are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs754002357; hg19: chr19-13008600;