chr19-12896249-G-C

Variant names:

• chr19-12896249-G-C
• rs121434373
• NM_000159.4:c.680G>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM5 PP3 PP5_Very_Strong

The NM_000159.4(GCDH):​c.680G>C​(p.Arg227Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000394 in 1,612,232 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000410865: Functional studies demonstrated that p.Arg227Pro variant is associated with low residual activity of glutaryl-CoA dehydrogenase (GCDH) compared to wildtype (Biery et al. 1996; Christensen et al. 1997; Liesert et al. 1999; Bijarnia et al. 2008; Flamand-Rouviere et al. 2010).; SCV000695722: A functional study, Biery_1996, supports these predictions with the observed significant decrease in GCDH activity. PMID:24896178; SCV000756255: Experimental studies have shown that this missense change affects GCDH function (PMID:8900227).; SCV000321706: Published functional studies demonstrate a reduction in glutaryl-CoA dehydrogenase enzyme activity by more than 95% (Biery et al., 1996);; SCV002064440: "This variant also showed reduced GCD activity by >95% when expressed in E coli (PMID:8900227)."". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R227L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 1.81
• Publications: 31 publications found

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 Gene-Disease associations (from GenCC):

• glutaryl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Myriad Women’s Health, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000410865: Functional studies demonstrated that p.Arg227Pro variant is associated with low residual activity of glutaryl-CoA dehydrogenase (GCDH) compared to wildtype (Biery et al. 1996; Christensen et al. 1997; Liesert et al. 1999; Bijarnia et al. 2008; Flamand-Rouviere et al. 2010).; SCV000695722: A functional study, Biery_1996, supports these predictions with the observed significant decrease in GCDH activity. PMID:24896178; SCV000756255: Experimental studies have shown that this missense change affects GCDH function (PMID: 8900227).; SCV000321706: Published functional studies demonstrate a reduction in glutaryl-CoA dehydrogenase enzyme activity by more than 95% (Biery et al., 1996);; SCV002064440: "This variant also showed reduced GCD activity by >95% when expressed in E coli (PMID: 8900227)."
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000159.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-12896249-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1498017.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799
• PP5: Variant 19-12896249-G-C is Pathogenic according to our data. Variant chr19-12896249-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000159.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCDH	NM_000159.4	MANE Select	c.680G>C	p.Arg227Pro	missense	Exon 8 of 12	NP_000150.1	Q92947-1
	GCDH	NM_013976.5		c.680G>C	p.Arg227Pro	missense	Exon 8 of 12	NP_039663.1	Q92947-2
	GCDH	NR_102316.1		n.843G>C		non_coding_transcript_exon	Exon 8 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCDH	ENST00000222214.10	TSL:1 MANE Select	c.680G>C	p.Arg227Pro	missense	Exon 8 of 12	ENSP00000222214.4	Q92947-1
	GCDH	ENST00000591470.5	TSL:1	c.680G>C	p.Arg227Pro	missense	Exon 7 of 11	ENSP00000466845.1	Q92947-1
	GCDH	ENST00000714069.1		c.680G>C	p.Arg227Pro	missense	Exon 8 of 13	ENSP00000519360.1	A0AAQ5BHD5

Frequencies

GnomAD3 genomes AF: 0.000246 AC: 37 AN: 150460 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

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: 0.000445

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000183 AC: 46 AN: 251378 AF XY: 0.000221

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000410 AC: 599 AN: 1461772 Hom.: 0 Cov.: 33 AF XY: 0.000422 AC XY: 307 AN XY: 727184

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.000134 AC: 6 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000508 AC: 565 AN: 1111954

Other (OTH) AF: 0.000431 AC: 26 AN: 60394

GnomAD4 genome AF: 0.000246 AC: 37 AN: 150460 Hom.: 0 Cov.: 31 AF XY: 0.000191 AC XY: 14 AN XY: 73476

African (AFR) AF: 0.000147 AC: 6 AN: 40778

American (AMR) AF: 0.0000661 AC: 1 AN: 15140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.00 AC: 0 AN: 4748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000445 AC: 30 AN: 67394

Other (OTH) AF: 0.00 AC: 0 AN: 2062

Alfa AF: 0.0000878 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Glutaric aciduria, type 1 (10)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		1.8
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.011	B
Vest4		0.66
MVP		0.87
MPC		0.52
ClinPred		0.20	T
GERP RS		0.23
Varity_R		0.97
gMVP		0.96
Mutation Taster		=16/84	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121434373; hg19: chr19-13007063; COSMIC: COSV53369235; COSMIC: COSV53369235;