9-6588403-C-T

Position:

chr9-6588403-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000170.3(GLDC):c.1705G>A(p.Ala569Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00492 in 1,609,056 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 41 hom. )

Consequence

GLDC
NM_000170.3 missense, splice_region

Scores

Splicing: ADA: 0.00002804

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:11

Conservation

PhyloP100: 0.438

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:

GLDC (HGNC:):

GLDC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014870584).

BP6

Variant 9-6588403-C-T is Benign according to our data. Variant chr9-6588403-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6588403-C-T is described in Lovd as [Benign]. Variant chr9-6588403-C-T is described in Lovd as [Likely_benign]. Variant chr9-6588403-C-T is described in Lovd as [Likely_pathogenic].

BS2

High Homozygotes in GnomAdExome4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLDC	NM_000170.3 linkuse as main transcript	c.1705G>A	p.Ala569Thr	missense_variant, splice_region_variant	14/25	ENST00000321612.8	NP_000161.2	P23378

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8 linkuse as main transcript	c.1705G>A	p.Ala569Thr	missense_variant, splice_region_variant	14/25	1	NM_000170.3	ENSP00000370737.4		P23378

Frequencies

GnomAD3 genomes

AF:

0.00396

AC:

603

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0176

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00478

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00430

AC:

1081

AN:

251442

Hom.:

AF XY:

0.00407

AC XY:

553

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0187

Gnomad NFE exome

AF:

0.00514

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00502

AC:

7318

AN:

1456856

Hom.:

Cov.:

AF XY:

0.00478

AC XY:

3469

AN XY:

725202

show subpopulations

Gnomad4 AFR exome

AF:

0.000719

Gnomad4 AMR exome

AF:

0.00141

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0198

Gnomad4 NFE exome

AF:

0.00537

Gnomad4 OTH exome

AF:

0.00380

GnomAD4 genome

AF:

0.00396

AC:

603

AN:

152200

Hom.:

Cov.:

AF XY:

0.00439

AC XY:

327

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0176

Gnomad4 NFE

AF:

0.00478

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00372

Hom.:

Bravo

AF:

0.00274

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00390

AC:

474

EpiCase

AF:

0.00425

EpiControl

AF:

0.00445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Uncertain:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycine encephalopathy

Pathogenic:1Uncertain:1Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Likely pathogenic, flagged submission	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 30, 2016	The c.1705G>A (p.Ala569Thr) missense variant in the GLDC gene is known and has been previously reported in at least 7 individuals affected with Glycine encephalopathy (Kure et al., 2006; Narisawa et al., 2012; Swanson et al., 2015). This variant has often been described in trans with another pathogenic variant (Pro765Ser, Pro304Leu) (Kure et al., 2006; Swanson et al., 2015). Multiple in vitro functional assays have demonstrated this variant results in reduced or undetectable GLDC activity (Narisawa et al., 2012; Swanson et al., 2015). This variant is reported at low frequency in the population databases (Exome Sequencing Project = 0.558%; 1000 Genomes = 0.7%; and ExAC = 0.454%). Therefore, this collective evidence supports the classification of the c.1705G>A (p.Ala569Thr) as a recessive Likely pathogenic variant for Glycine encephalopathy. We have confirmed this finding in our laboratory using Sanger sequencing. -
Uncertain significance, flagged submission	clinical testing	Natera, Inc.	Oct 09, 2019	- -

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 12, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	GLDC: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 04, 2018	This variant is associated with the following publications: (PMID: 26179960, 22171071, 16450403, 27362913) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 27, 2022

Variant summary: GLDC c.1705G>A (p.Ala569Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0043 in 252282 control chromosomes in the gnomAD database, including 8 homozygotes. The observed variant frequency is approximately 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. c.1705G>A has been reported in the literature in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) without strong evidence for causality (e.g. Kure_2006, Narisawa_2012, Swanson_2015). Functional studies assessing the impact of the variant on protein function have reported 40-75% enzyme activity and normal protein levels (Swanson_2015, Narisawa_2012). Nine assessments for this variant have been submitted to ClinVar after 2014 with conflicting assessments (benign n=3, likely benign n=4, VUS n=1, likely pathogenic n=1). Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Benign

8.7

DANN

Benign

0.94

DEOGEN2

Benign

0.25

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.40

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.011

MutationAssessor

Benign

0.64

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.36

REVEL

Uncertain

0.58

Sift

Benign

0.085

Sift4G

Benign

0.083

Polyphen

0.0

Vest4

0.21

MVP

0.90

MPC

0.045

ClinPred

0.017

GERP RS

-4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.099

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000028

dbscSNV1_RF

Benign

0.016

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