9-6645324-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_000170.3(GLDC):c.176G>C(p.Arg59Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,431,718 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GLDC
NM_000170.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 2.82

Publications

2 publications found

Variant links:

Genes affected

GLDC (HGNC:4313): (glycine decarboxylase) Degradation of glycine is brought about by the glycine cleavage system, which is composed of four mitochondrial protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide dehydrogenase). The protein encoded by this gene is the P protein, which binds to glycine and enables the methylamine group from glycine to be transferred to the T protein. Defects in this gene are a cause of nonketotic hyperglycinemia (NKH).[provided by RefSeq, Jan 2010]

GLDC Gene-Disease associations (from GenCC):

glycine encephalopathy
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen
glycine encephalopathy 1
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
infantile glycine encephalopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
neonatal glycine encephalopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
atypical glycine encephalopathy
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

GLDC links:

LINC02851 (HGNC:):

LINC02851 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.756

PP5

Variant 9-6645324-C-G is Pathogenic according to our data. Variant chr9-6645324-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 56049.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3 link	c.176G>C	p.Arg59Thr	missense_variant	Exon 1 of 25	ENST00000321612.8	NP_000161.2	P23378

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GLDC	ENST00000321612.8 link	c.176G>C	p.Arg59Thr	missense_variant	Exon 1 of 25	1	NM_000170.3	ENSP00000370737.4	P23378
LINC02851	ENST00000813373.1 link	n.124+398C>G		intron_variant	Intron 1 of 2
LINC02851	ENST00000813380.1 link	n.405+398C>G		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1431718

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

710290

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31736

American (AMR)

AF:

0.00

AC:

AN:

41052

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25376

East Asian (EAS)

AF:

0.00

AC:

AN:

37624

South Asian (SAS)

AF:

0.00

AC:

AN:

82110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50768

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4460

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1099482

Other (OTH)

AF:

0.00

AC:

AN:

59110

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycine encephalopathy

Pathogenic:2

Feb 28, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM3,PM2,PS1,PP3. -

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inborn genetic diseases

Uncertain:1

Oct 10, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.176G>C (p.R59T) alteration is located in exon 1 (coding exon 1) of the GLDC gene. This alteration results from a G to C substitution at nucleotide position 176, causing the arginine (R) at amino acid position 59 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.31

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.76

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

0.0

PhyloP100

2.8

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.61

Sift

Benign

0.76

Sift4G

Benign

0.52

Polyphen

0.049

Vest4

0.77

MutPred

0.72

Gain of glycosylation at R59 (P = 0.0276);

MVP

0.94

MPC

0.21

ClinPred

0.94

GERP RS

5.0

PromoterAI

-0.0092

Neutral

(source)

Varity_R

0.81

gMVP

0.70

Mutation Taster

=21/79

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over