rs748185335

Variant names:

• chr19-12891930-A-C
• rs748185335
• NM_000159.4:c.227A>C

Your query was ambiguous. Multiple possible variants found:

• chr19-12891930-A-C
• chr19-12891930-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000159.4(GCDH):​c.227A>C​(p.Gln76Pro) variant causes a missense change involving the alteration of a 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.76

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 6 ACMG points.

• PM1: In a helix (size 16) in uniprot entity GCDH_HUMAN there are 6 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, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCDH	NM_000159.4	c.227A>C	p.Gln76Pro	missense_variant	Exon 4 of 12	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5	c.227A>C	p.Gln76Pro	missense_variant	Exon 4 of 12		NP_039663.1
GCDH	NR_102316.1	n.335A>C		non_coding_transcript_exon_variant	Exon 4 of 12
GCDH	NR_102317.1	n.643A>C		non_coding_transcript_exon_variant	Exon 3 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10	c.227A>C	p.Gln76Pro	missense_variant	Exon 4 of 12	1	NM_000159.4	ENSP00000222214.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GCDH c.227A>C (p.Gln76Pro) results in a non-conservative amino acid change in 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 251416 control chromosomes (gnomAD). c.227A>C has been reported in the literature in one homozygous individual affected with Glutaric Acidemia Type 1 (Abdul Wahab_2016). These data indicate that the variant may 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: 27672653, 37020324, 38137040). ClinVar contains an entry for this variant (Variation ID: 553050). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Glutaric aciduria, type 1 Uncertain:1

Jul 25, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.;D;D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	.;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.5	H;.;H;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.4	D;.;.;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;.;.;.;.
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		0.72	P;.;P;.;.
Vest4		0.83
MutPred		0.60		Gain of phosphorylation at T73 (P = 0.1168);Gain of phosphorylation at T73 (P = 0.1168);Gain of phosphorylation at T73 (P = 0.1168);.;Gain of phosphorylation at T73 (P = 0.1168);
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		0.92

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: rs748185335; hg19: chr19-13002744;