9-6556242-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000170.3(GLDC):c.2113G>A(p.Val705Met) variant causes a missense change. The variant allele was found at a frequency of 0.00281 in 1,611,080 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0036 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 25 hom. )

Consequence

GLDC
NM_000170.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 5.81

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015131503).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00364 (554/152296) while in subpopulation AMR AF= 0.00733 (112/15286). AF 95% confidence interval is 0.00623. There are 5 homozygotes in gnomad4. There are 303 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3 link	c.2113G>A	p.Val705Met	missense_variant	Exon 18 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.2113G>A	p.Val705Met	missense_variant	Exon 18 of 25	1	NM_000170.3	ENSP00000370737.4		P23378

Frequencies

GnomAD3 genomes

AF:

0.00365

AC:

555

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00734

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.00315

Gnomad OTH

AF:

0.00573

GnomAD3 exomes

AF:

0.00370

AC:

930

AN:

251452

Hom.:

AF XY:

0.00376

AC XY:

511

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00269

Gnomad ASJ exome

AF:

0.00952

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00291

Gnomad FIN exome

AF:

0.0102

Gnomad NFE exome

AF:

0.00336

Gnomad OTH exome

AF:

0.00684

GnomAD4 exome

AF:

0.00273

AC:

3978

AN:

1458784

Hom.:

Cov.:

AF XY:

0.00285

AC XY:

2072

AN XY:

725906

show subpopulations

Gnomad4 AFR exome

AF:

0.00132

Gnomad4 AMR exome

AF:

0.00288

Gnomad4 ASJ exome

AF:

0.0103

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00325

Gnomad4 FIN exome

AF:

0.0109

Gnomad4 NFE exome

AF:

0.00201

Gnomad4 OTH exome

AF:

0.00430

GnomAD4 genome

AF:

0.00364

AC:

554

AN:

152296

Hom.:

Cov.:

AF XY:

0.00407

AC XY:

303

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00733

Gnomad4 ASJ

AF:

0.0121

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00353

Gnomad4 FIN

AF:

0.0120

Gnomad4 NFE

AF:

0.00315

Gnomad4 OTH

AF:

0.00567

Alfa

AF:

0.00286

Hom.:

Bravo

AF:

0.00331

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00365

AC:

443

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00480

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GLDC c.2113G>A (p.Val705Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0037 in 251452 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in GLDC causing Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) phenotype (0.0031), strongly suggesting that the variant is benign. Although reported in the literature, to our knowledge, no penetrant association of c.2113G>A in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Glycine encephalopathy

Uncertain:1Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 11, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Benign:2

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GLDC: BS2 -

Oct 02, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28116331, 27362913, 27884173, 16601880) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.0098

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;.;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D;D

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

2.9

M;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.4

N;.;.

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0040

D;.;.

Sift4G

Uncertain

0.0080

D;.;.

Polyphen

0.95

P;.;.

Vest4

0.90

MVP

0.98

MPC

0.25

ClinPred

0.021

GERP RS

4.5

Varity_R

0.45

gMVP

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over