19-12897859-C-A

Position:

• chr19-12897859-C-A

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.1239C>A​(p.Tyr413Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y413Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GCDH NM_000159.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.990

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 does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 43 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-12897859-C-A is Pathogenic according to our data. Variant chr19-12897859-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12897859-C-A is described in Lovd as [Pathogenic]. Variant chr19-12897859-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCDH	NM_000159.4	c.1239C>A	p.Tyr413Ter	stop_gained	11/12	ENST00000222214.10
GCDH	NM_013976.5	c.1239C>A	p.Tyr413Ter	stop_gained	11/12
GCDH	NR_102316.1	n.1402C>A		non_coding_transcript_exon_variant	11/12
GCDH	NR_102317.1	n.1620C>A		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.1239C>A	p.Tyr413Ter	stop_gained	11/12	1	NM_000159.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

Counsyl

Nov 21, 2014

- -

GCDH-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 2022

The GCDH c.1239C>A variant is predicted to result in premature protein termination (p.Tyr413*). This variant was reported in a study of individuals with an individual with glutaric acidemia type 1, although no additional functional or segregation data was reported (Zschocke et al. 2000. PubMed ID: 10699052). It was also reported in the homozygous state in an individual identified based on abnormal newborn screen results suggestive of glutaric acidemia type 1 (Harting et al. 2009. PubMed ID: 19433437). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. Nonsense variants in GCDH are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DANN	Uncertain	0.98
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.26	N
MutationTaster	Benign	1.0	D;D;D;D
Vest4		0.90
GERP RS		-7.0

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: rs776082304; hg19: chr19-13008673;