9-6534775-G-T

Position:

chr9-6534775-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_000170.3(GLDC):c.2852C>A(p.Ser951Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000444 in 1,597,928 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 0 hom. )

Consequence

GLDC
NM_000170.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:8

Conservation

PhyloP100: 9.11

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-6534775-G-T is Pathogenic according to our data. Variant chr9-6534775-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554247.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, Pathogenic=1, Likely_pathogenic=5}. Variant chr9-6534775-G-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.18011269). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLDC	NM_000170.3 linkuse as main transcript	c.2852C>A	p.Ser951Tyr	missense_variant	24/25	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.2852C>A	p.Ser951Tyr	missense_variant	24/25	1	NM_000170.3	ENSP00000370737.4		P23378

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000338

AC:

AN:

251124

Hom.:

AF XY:

0.000391

AC XY:

AN XY:

135720

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.000648

Gnomad NFE exome

AF:

0.000467

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000452

AC:

654

AN:

1445614

Hom.:

Cov.:

AF XY:

0.000467

AC XY:

336

AN XY:

720242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000905

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000140

Gnomad4 FIN exome

AF:

0.000956

Gnomad4 NFE exome

AF:

0.000490

Gnomad4 OTH exome

AF:

0.000517

GnomAD4 genome

AF:

0.000361

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000531

Hom.:

Bravo

AF:

0.000484

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000329

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycine encephalopathy

Pathogenic:3Uncertain:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Feb 28, 2023	GLDC NM_000170.2 p.Ser951Tyr (c.2852C>A): This variant has been reported in the literature in trans with a pathogenic variant in 1 individual with nonketotic hyperglycinemia (NKH), in the heterozygous state in 1 individual with features suggestive of NKH, and in trans with a pathogenic variant in multiple individuals with NKH at a commercial laboratory (del Toro 2006 PMID: 16802295; Coughlin 2017 PMID: 27362913; GeneDx, personal communication). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.08% [12/15282]; https://gnomad.broadinstitute.org/variant/9-6534775-G-T?dataset=gnomad_r3); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. It is also present in ClinVar, with classifications ranging from VUS to pathogenic (Variation ID: 554247). Evolutionary conservation and computational predictive tools for this variant weakly suggest that it might impact protein structure or function. An in vitro functional study found that cells with this variant had approximately 39% residual enzymatic activity compared to the wild-type (del Toro 2006 PMID: 16802295). Mouse models have supported this, showing that this variant results in mild but still significant elevation of plasma glycine compared to the wild-type, as well as increased glycine accumulation in the brain (Leung 2020 PMID: 32743799). However, these studies may not accurately represent biological function in humans. Based on the above data, this variant is classified as likely pathogenic but may also be considered hypomorphic, likely causing disease when in trans with a more deleterious pathogenic variant. -
Uncertain significance, 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 03, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 18, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 951 of the GLDC protein (p.Ser951Tyr). This variant is present in population databases (rs147472391, gnomAD 0.07%). This missense change has been observed in individual(s) with glycine encephalopathy and/or nonketotic hyperglycinemia (PMID: 27362913). 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: 554247). 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 not expected to disrupt GLDC protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GLDC function (PMID: 16802295). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Feb 26, 2021	The c.2852C>A (p.Ser951Tyr) variant identified in the GLDC gene substitutes a moderately conserved Serine for Tyrosine at amino acid 951/1021 (exon 24/25). This variant is found with low frequency in gnomAD(v3.1) (55 heterozygotes, 0 homozygotes, allele frequency: 3.6e-4) suggesting it is not a common benign variant in the populations represented in that databases. In silico algorithms predict this variant to be Damaging (SIFT; score: 0.00) and Pathogenic (REVEL; score: 0.6449) to the function of the canonical transcript. This variant is reported in ClinVar as a Variant of Uncertain Significance (VarID:554247), and has been reported in 2 individuals with Glycine Encephalopathy [PMID:16802295; PMID:27362913], and has also been observed in a fetus with anencephaly [PMID:29205322], although its clinical relevance to the anencephaly phenotype is unclear. Expression analysis in COS-7 cells from an individual with the p.Ser951Tyr variant suggest this variant has approximately 39% residual enzyme activity [PMID:16802295], and this finding is supported by recent studies in an equivalent mouse model (GldcS956Ymice) [PMID:32743799]. The c.2852C>A (p.Ser951Tyr) variant identified in the GLDC gene is reported as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 06, 2021	- -

Glycine encephalopathy 1

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Feb 21, 2024	This variant has been reported in the literature in trans (on opposite alleles) with a pathogenic variant in one individual with nonketotic hyperglycinemia (NKH), in the heterozygous state in one individual with features suggestive of NKH, and in trans with a pathogenic variant in an individual with NKH at a commercial laboratory (del Toro 2006 PMID: 16802295; Coughlin 2017 PMID: 27362913; ClinVar Variation ID: 554247). It is present in gnomAD (Highest reported MAF, non-bottlenecked: 0.05% [570/1165280]; https://gnomad.broadinstitute.org/variant/9-6534775-G-T?dataset=gnomad_r4); please note, disease-causing variants may be present in control databases at low frequencies, reflective of carrier status, incomplete penetrance, and/or variable expressivity. An in vitro functional study found that this variant confers approximately 39% residual enzyme activity compared to the wild type (del Toro 2006 PMID: 16802295). Mouse models have supported this, showing that this variant results in mild but still significant elevation of plasma glycine compared to the wild type, as well as increased glycine accumulation in the brain (Leung 2020 PMID: 32743799). Evolutionary conservation and computational predictive tools for this variant weakly support a potential deleterious effect on protein structure or function. The experimental data available for this variant and other variants with similar effects on enzyme activity are consistent with this variant resulting in an attenuated NKH phenotype when homozygous or compound heterozygous with another variant with residual enzyme activity (Coughlin 2017 PMID: 27362913). In summary, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 15, 2024	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 16802295, 32743799) -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2024	Published functional studies demonstrate a damaging effect, specifically mice with the variant, showing an accumulation of glycine in the liver and brain (PMID: 32743799); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27362913, 16802295, 29988937, 29205322, 32743799) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 28, 2022

Variant summary: GLDC c.2852C>A (p.Ser951Tyr) results in a non-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 0.00034 in 251124 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GLDC causing Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (0.00034 vs 0.0031), allowing no conclusion about variant significance. c.2852C>A has been reported in the literature in individuals affected with Non-Ketotic Hyperglycinemia (del Toro_2006, Coughlin_2017) and in one individual with anencephaly (Ishida_2018). These data indicate that the variant may be associated with disease. An assay using transiently transfected COS7 cells showed that the variant had 39% enzymatic activity compared to wild type (del Toro_2006). Additionally, a mouse model found that animals carrying the corresponding variant in mouse Gldc in compound heterozygosity with a null allele had glycine accumulation at 1.3-fold what is seen in control animals (Leung_2020). Nine ClinVar submitters have assessed the variant since 2014: seven classified the variant as VUS, one as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2021

The c.2852C>A (p.S951Y) alteration is located in exon 24 (coding exon 24) of the GLDC gene. This alteration results from a C to A substitution at nucleotide position 2852, causing the serine (S) at amino acid position 951 to be replaced by a tyrosine (Y). 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

Pathogenic

0.72

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

D;.;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.18

T;T;T;T

MetaSVM

Uncertain

0.37

MutationAssessor

Benign

1.5

L;.;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.1

D;.;.;.

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

D;.;.;.

Sift4G

Pathogenic

0.0

D;.;.;.

Polyphen

0.94

P;.;.;.

Vest4

0.71

MVP

0.95

MPC

0.18

ClinPred

0.18

GERP RS

4.5

Varity_R

0.80

gMVP

0.91

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