9-6595046-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000170.3(GLDC):c.1229G>A(p.Arg410Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00114 in 1,611,492 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign 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. R410S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0026 ( 6 hom., cov: 33)

Exomes 𝑓: 0.00098 ( 15 hom. )

Consequence

GLDC
NM_000170.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 7.20

Publications

7 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 9-6595046-C-T is Benign according to our data. Variant chr9-6595046-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225378.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0026 (396/152280) while in subpopulation AMR AF = 0.022 (336/15300). AF 95% confidence interval is 0.02. There are 6 homozygotes in GnomAd4. There are 200 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3 link	c.1229G>A	p.Arg410Lys	missense_variant	Exon 9 of 25	ENST00000321612.8	NP_000161.2	P23378

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8 link	c.1229G>A	p.Arg410Lys	missense_variant	Exon 9 of 25	1	NM_000170.3	ENSP00000370737.4		P23378

Frequencies

GnomAD3 genomes

AF:

0.00262

AC:

398

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0221

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00385

AC:

966

AN:

251170

AF XY:

0.00277

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0262

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.000924

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.000985

AC:

1437

AN:

1459212

Hom.:

Cov.:

AF XY:

0.000804

AC XY:

584

AN XY:

726126

show subpopulations

African (AFR)

AF:

0.000359

AC:

AN:

33414

American (AMR)

AF:

0.0274

AC:

1227

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000345

AC:

AN:

26116

East Asian (EAS)

AF:

0.00116

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1109630

Other (OTH)

AF:

0.00187

AC:

113

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

100

199

299

398

498

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00260

AC:

396

AN:

152280

Hom.:

Cov.:

AF XY:

0.00269

AC XY:

200

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000746

AC:

AN:

41556

American (AMR)

AF:

0.0220

AC:

336

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68018

Other (OTH)

AF:

0.00616

AC:

AN:

2112

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

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000923

Hom.:

Bravo

AF:

0.00475

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00285

AC:

346

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycine encephalopathy

Uncertain:1Benign:5

Jan 09, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The homozygous p.Arg410Lys variant in GLDC has been identified in an individual with non-ketotic hyperglycinaemia (PMID: 12126939), but has also been identified in >2% of Latino chromosomes and 8 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive non-ketotic hyperglycinaemia. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:reference population

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jul 13, 2023

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Jul 02, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 20, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29153744, 27535533, 27362913, 12126939) -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GLDC: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

D;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.42

MutationAssessor

Uncertain

2.0

M;.

PhyloP100

7.2

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.4

N;.

REVEL

Pathogenic

0.76

Sift

Benign

0.053

T;.

Sift4G

Benign

0.086

T;.

Polyphen

0.39

B;.

Vest4

0.78

MVP

0.97

MPC

0.10

ClinPred

0.059

GERP RS

4.7

Varity_R

0.79

gMVP

0.83

Mutation Taster

=51/49

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.35

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over