rs121964976

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000170.3(GLDC):c.1545G>C(p.Arg515Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000328 in 1,610,010 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R515R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

GLDC
NM_000170.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 0.614

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 9-6589230-C-G is Pathogenic according to our data. Variant chr9-6589230-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 11985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6589230-C-G is described in Lovd as [Pathogenic]. Variant chr9-6589230-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLDC	NM_000170.3 link	c.1545G>C	p.Arg515Ser	missense_variant	12/25	ENST00000321612.8	NP_000161.2	P23378

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8 link	c.1545G>C	p.Arg515Ser	missense_variant	12/25	1	NM_000170.3	ENSP00000370737.4		P23378

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251474

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000353

AC:

515

AN:

1457968

Hom.:

Cov.:

AF XY:

0.000357

AC XY:

259

AN XY:

725660

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000458

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycine encephalopathy

Pathogenic:9Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This established pathogenic variant has been reported in individuals with glycine encephalopathy (nonketotic hyperglycinemia) (PMID: 17361008, 26179960, 11286506), and identified as a founder variant in the United Kingdom (PMID: 20301531, 27362913). Functional studies have shown that this variant leads to a protein with no measurable residual functional activity (PMID: 26179960). The c.1545G>C (p.Arg515Ser) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0088% (25/282836) and is absent in the homozygous state. It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1545G>C (p.Arg515Ser) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 29, 2018	Variant summary: GLDC c.1545G>C (p.Arg515Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9e-05 in 277284 control chromosomes (gnomAD and publication). The variant, c.1545G>C, has been reported in the literature in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia)(Sellner_2005, Toone_2001). It has also been reported as a commonly observed missesne variant present in six percent of all GLDC alleles (PMID: 27362913, Coughlin et al, 2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 31, 2018	The GLDC c.1545G>C (p.Arg515Ser) variant has been reported in five studied and was found in a total of 60 probands including four in a homozygous state, 48 in a compound heterozygous state, and 11 in a heterozygous state with an undetected second allele (Toone et al. 2000; Toone et al. 2001, Sellner et al. 2005; Kanno et al. 2007; Coughlin et al. 2016). A large deletion may not have been identified in the heterozygous probands with the testing methods used (Toone et al. 2001, Sellner et al. 2005). The p.Arg515Ser variant is identified as a founder variant in the United Kingdom (Coughlin et al. 2016). Control data are unavailable for the p.Arg515Ser variant, which is reported at a frequency of 0.000189 in the European (non-Finnish) population of the Genome Aggregation Database. The crystal structure of the p.Arg515Ser variant predicts the variant protein to be destabilized (Nakai et al. 2005). Based on the evidence, the p.Arg515Ser variant is classified as pathogenic for glycine encephalopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 515 of the GLDC protein (p.Arg515Ser). This variant is present in population databases (rs121964976, gnomAD 0.02%). This missense change has been observed in individual(s) with glycine encephalopathy (nonketotic hyperglycininemia) (PMID: 10873393, 11286506, 12126939, 17361008, 26179960; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 11985). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLDC protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 02, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 01, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Apr 26, 2021	ACMG codes:PS3, PS4, PM2, PM3, PP3, PP5 -

Glycine encephalopathy 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 04, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2001	- -

Generalized epilepsy;C0028754:Obesity;C0557874:Global developmental delay

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Claritas Genomics

Nov 28, 2016

The c.1545G>C (p.Arg515Ser) missense variant in the GLDC gene is previously reported in the literature and is a recognized cause of nonketotic hyperglycinemia. Homozygous and compound heterozygous loss-of-function pathogenic variants in this gene are associated with nonketotic hyperglycinemia, also known as glycine encephalopathy. This variant has been observed at a high frequency among individuals with nonketotic hyperglycinemia and has been seen in both the homozygous and compound heterozygous state with other known pathogenic variants, including large exonic deletions. Functional studies have shown that the presence of this variant causes the protein to be unstable with no residual functional activity. This variant has not been observed in either 1000 Genomes or NHLBI Exome Sequencing Project datasets, but has been observed in ExAC at an allele frequency of 0.00015, with no homozygotes reported. This variant involves a weakly conserved nucleotide but highly conserved amino acid. PolyPhen-2, SIFT, and MutationTaster all predict this variant to be damaging. Therefore, based on the reports and functional evidence in the literature, this variant is classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 02, 2022

Published functional studies demonstrate a damaging effect with significant impairment of enzyme function (Swanson et al., 2015); In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect; This variant is associated with the following publications: (PMID: 10873393, 11286506, 15272469, 33524012, 26179960, 12126939, 15670722, 28794088, 20301531, 17361008, 32421718, 27362913) -

GLDC-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 31, 2023

The GLDC c.1545G>C variant is predicted to result in the amino acid substitution p.Arg515Ser. This variant is one of the most common pathogenic variants for non-ketotic hyperglycinaemia, also known as glycine encephalopathy (Toone et al. 2000. PubMed ID: 10873393; Coughlin et al. 2017. PubMed ID: 27362913; Van Hove et al. 2019. PubMed ID: 20301531). Experimental studies indicate the p.Arg515Ser substitution impairs enzyme stability and function (Toone et al. 2000. PubMed ID: 10873393; Swanson et al. 2015. PubMed ID: 26179960). It is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-6589230-C-G). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.47

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

Eigen

Benign

0.0028

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.99

MutPred

0.80

Gain of disorder (P = 0.0379);

MVP

0.97

MPC

0.33

ClinPred

0.85

GERP RS

-2.2

Varity_R

0.96

gMVP

0.96

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