rs964724051

chr19-12896269-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000159.4(GCDH):c.700C>T(p.Arg234Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,746 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R234P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 2.90

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000159.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-12896270-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1502957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 19-12896269-C-T is Pathogenic according to our data. Variant chr19-12896269-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 552581.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}. Variant chr19-12896269-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCDH	NM_000159.4	c.700C>T	p.Arg234Trp	missense_variant	8/12	ENST00000222214.10
GCDH	NM_013976.5	c.700C>T	p.Arg234Trp	missense_variant	8/12
GCDH	NR_102316.1	n.863C>T		non_coding_transcript_exon_variant	8/12
GCDH	NR_102317.1	n.1081C>T		non_coding_transcript_exon_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.700C>T	p.Arg234Trp	missense_variant	8/12	1	NM_000159.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461746 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:4 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 24, 2023	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GCDH protein function. ClinVar contains an entry for this variant (Variation ID: 552581). This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 25190159, 30570710; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 234 of the GCDH protein (p.Arg234Trp). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 21, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 07, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 21, 2023	Variant summary: GCDH c.700C>T (p.Arg234Trp) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, central domain (IPR006091) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251420 control chromosomes. c.700C>T has been reported in the literature in individuals affected with Glutaric Acidemia Type 1 (e.g., Wang_2014, Pokora_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33728242, 30570710, 25190159). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (Pathogenic, n = 1; Likely pathogenic, n = 1; Uncertain significance, n = 1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-7.4	D;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.65		Loss of MoRF binding (P = 0.1697);Loss of MoRF binding (P = 0.1697);
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.94
gMVP		0.92

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: rs964724051; hg19: chr19-13007083; COSMIC: COSV53368672; COSMIC: COSV53368672;