rs776082304

Variant names:

• chr19-12897859-C-A
• rs776082304
• NM_000159.4:c.1239C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-12897859-C-A
• chr19-12897859-C-G
• chr19-12897859-C-T

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.Tyr413*) 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 (★★).

• 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:3
• 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 28 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 rank	MANE	Protein	UniProt
GCDH	NM_000159.4	c.1239C>A	p.Tyr413*	stop_gained	Exon 11 of 12	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5	c.1239C>A	p.Tyr413*	stop_gained	Exon 11 of 12		NP_039663.1
GCDH	NR_102316.1	n.1402C>A		non_coding_transcript_exon_variant	Exon 11 of 12
GCDH	NR_102317.1	n.1620C>A		non_coding_transcript_exon_variant	Exon 10 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10	c.1239C>A	p.Tyr413*	stop_gained	Exon 11 of 12	1	NM_000159.4	ENSP00000222214.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

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:2

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr413*) in the GCDH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acid(s) of the GCDH protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with glutaric acidemia type I (PMID: 10699052). ClinVar contains an entry for this variant (Variation ID: 189066). This variant disrupts a region of the GCDH protein in which other variant(s) (p.Ala433Val) have been determined to be pathogenic (PMID: 10960496, 12948740, 21176883, 29201125, 31952437). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Nov 21, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

GCDH-related disorder Pathogenic:1

Nov 20, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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;