rs1176799813

Positions:

• chr19-12893627-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000159.4(GCDH):​c.479A>G​(p.Gln160Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,982 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 6.96

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]

GCDH (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a helix (size 11) in uniprot entity GCDH_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000159.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 19-12893627-A-G is Pathogenic according to our data. Variant chr19-12893627-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 529445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12893627-A-G is described in Lovd as [Pathogenic]. Variant chr19-12893627-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCDH	NM_000159.4	c.479A>G	p.Gln160Arg	missense_variant	6/12	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5	c.479A>G	p.Gln160Arg	missense_variant	6/12		NP_039663.1
GCDH	NR_102316.1	n.642A>G		non_coding_transcript_exon_variant	6/12
GCDH	NR_102317.1	n.895A>G		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10	c.479A>G	p.Gln160Arg	missense_variant	6/12	1	NM_000159.4	ENSP00000222214.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74328

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:4 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2024	Variant summary: GCDH c.479A>G (p.Gln160Arg) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251384 control chromosomes (gnomAD). c.479A>G has been reported in the literature in a homozygous individual affected with Glutaric Acidemia Type 1 (Holiner_2010). These data indicate that the variant may be associated with disease. An enzymatic assay using skin fibroblasts from the patient showed a complete lack of GCDH activity. The following publication has been ascertained in the context of this evaluation (PMID: 20084589). ClinVar contains an entry for this variant (Variation ID: 529445). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 03, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2023	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 160 of the GCDH protein (p.Gln160Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glutaric acidemia, type I (PMID: 20084589; Invitae). ClinVar contains an entry for this variant (Variation ID: 529445). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, flagged submission	clinical testing	Counsyl	Jan 03, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 31, 2024	- -

Tyrosinemia type III Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 28, 2024

Variant summary: HPD c.479A>G (p.Tyr160Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251546 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.479A>G has been reported in the literature in two homozygous individuals (siblings) affected with Tyrosinemia Type 3 (Ruetschi_2000) as well as in one homozygous individual with no clinical symptoms and with normal mental development (Szymanska_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.8	H;.;H;.
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.8	D;.;.;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.99	D;.;D;.
Vest4		0.44
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.99

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: rs1176799813; hg19: chr19-13004441;