rs1176799813

chr19-12893627-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 529445.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=1, Uncertain_significance=1}. 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	UniProt
GCDH	NM_000159.4	c.479A>G	p.Gln160Arg	missense_variant	6/12	ENST00000222214.10
GCDH	NM_013976.5	c.479A>G	p.Gln160Arg	missense_variant	6/12
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	Appris	UniProt
GCDH	ENST00000222214.10	c.479A>G	p.Gln160Arg	missense_variant	6/12	1	NM_000159.4	P1

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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, criteria provided, single submitter	clinical testing	Counsyl	Jan 03, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 30, 2023	- -
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. c.479A>G has been reported in the literature in individuals affected with Glutaric Acidemia Type 1. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. ClinVar contains an entry for this variant (Variation ID: 529445). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Tyrosinemia type III Pathogenic:1

Likely pathogenic, criteria provided, single submitter

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
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;.
MutationTaster	Benign	1.0	D;D;D;D
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;