rs1197426645

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_000159.4(GCDH):c.1A>C(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.0000165 in 1,453,548 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: not found (cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

GCDH
NM_000159.4 initiator_codon

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.51

Publications

1 publications found

Variant links:

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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, Myriad Women’s Health

GCDH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 40 pathogenic variants. Next in-frame start position is after 80 codons. Genomic position: 12891941. Lost 0.181 part of the original CDS.

PS1

Another start lost variant in NM_000159.4 (GCDH) was described as [Likely_pathogenic] in ClinVar as 2577569

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-12891305-A-C is Pathogenic according to our data. Variant chr19-12891305-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552917.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GCDH	NM_000159.4 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 12	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 12		NP_039663.1
GCDH	NR_102316.1 link	n.109A>C		non_coding_transcript_exon_variant	Exon 2 of 12
GCDH	NR_102317.1 link	n.109A>C		non_coding_transcript_exon_variant	Exon 2 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 12	1	NM_000159.4	ENSP00000222214.4		Q92947-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000165

AC:

AN:

1453548

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

723482

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33432

American (AMR)

AF:

0.00

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46902

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4810

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1111508

Other (OTH)

AF:

0.00

AC:

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Glutaric aciduria, type 1

Pathogenic:2

Dec 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the GCDH mRNA. The next in-frame methionine is located at codon 80. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with glutaric acidemia type I (PMID: 29665094). ClinVar contains an entry for this variant (Variation ID: 552917). This variant disrupts the p.Trp50 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jul 18, 2017

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.40

T;.;T;T;T

Eigen

Benign

0.18

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

.;D;D;D;D

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.0

PhyloP100

4.5

PROVEAN

Benign

-0.50

N;.;.;.;.

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;.;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;T;D

Polyphen

0.85

P;.;P;.;.

Vest4

0.80

MutPred

0.97

Gain of stability (P = 0.0591);Gain of stability (P = 0.0591);Gain of stability (P = 0.0591);Gain of stability (P = 0.0591);Gain of stability (P = 0.0591);

MVP

0.98

ClinPred

1.0

GERP RS

3.9

PromoterAI

-0.00040

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.72

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

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

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rs1197426645

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over