chr9-6534775-G-T

Variant names:

• chr9-6534775-G-T
• rs147472391
• NM_000170.3:c.2852C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP5 BP4

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). Synonymous variant affecting the same amino acid position (i.e. S951S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:9
• Conservation: PhyloP100: 9.11
• Publications: 5 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000170.3
• 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 VariationId is 554247.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18011269). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000170.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	NM_000170.3	MANE Select	c.2852C>A	p.Ser951Tyr	missense	Exon 24 of 25	NP_000161.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	ENST00000321612.8	TSL:1 MANE Select	c.2852C>A	p.Ser951Tyr	missense	Exon 24 of 25	ENSP00000370737.4
	GLDC	ENST00000638233.1	TSL:1	n.1287C>A		non_coding_transcript_exon	Exon 10 of 11
	GLDC	ENST00000639443.1	TSL:1	n.2420C>A		non_coding_transcript_exon	Exon 20 of 21

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152196 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000338 AC: 85 AN: 251124 AF XY: 0.000391

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 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.: 0 Cov.: 27 AF XY: 0.000467 AC XY: 336 AN XY: 720242

African (AFR) AF: 0.0000905 AC: 3 AN: 33132

American (AMR) AF: 0.000380 AC: 17 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85886

European-Finnish (FIN) AF: 0.000956 AC: 51 AN: 53370

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5738

European-Non Finnish (NFE) AF: 0.000490 AC: 538 AN: 1097258

Other (OTH) AF: 0.000517 AC: 31 AN: 59906

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74472

African (AFR) AF: 0.000144 AC: 6 AN: 41588

American (AMR) AF: 0.000784 AC: 12 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000324 Hom.: 3

Bravo AF: 0.000484

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000329 AC: 40

EpiCase AF: 0.000654

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycine encephalopathy Pathogenic:2 Uncertain:4

Feb 26, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jan 18, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 28, 2023

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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.

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GLDC protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GLDC function (PMID: 16802295). For these reasons, this variant has been classified as Pathogenic.

Glycine encephalopathy 1 Pathogenic:3 Uncertain:2

Oct 03, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Feb 21, 2024

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Oct 27, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Aug 06, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1 Uncertain:1

Oct 15, 2024

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Jun 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 19, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This frequency is not significantly higher than estimated 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, Drackley_2024), and anencephaly (Ishida_2018). At-least one patient with severe Nonketotic hyperglycinemia was homozygous for this variant and a causal variant in AMT (Drackley_2024). 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). The following publications have been ascertained in the context of this evaluation (PMID: 27362913, 29205322, 32743799, 16802295, 38572626). ClinVar contains an entry for this variant (Variation ID: 554247). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Inborn genetic diseases Uncertain:1

Aug 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 data from gnomAD, the A allele has an overall frequency of 0.033% (94/282516) total alleles studied. The highest observed frequency was 0.06% (15/25086) of European (Finnish) alleles. This variant has been identified in the homozygous state and/or in conjunction with other GLDC variant(s) in individual(s) with features consistent with glycine encephalopathy; in at least one instance, the variants were identified in trans (Coughlin, 2017). This amino acid position is not well conserved in available vertebrate species. Functional studies suggest a partial loss of function; however, additional evidence is needed to confirm this finding (del Toro, 2006). An animal model expressing this variant exhibited biochemical phenotype(s) consistent with GLDC-related disease (Leung, 2020). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.5	L
PhyloP100		9.1
PrimateAI	Uncertain	0.64	T
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	T
GERP RS		4.5
PromoterAI		0.0028	Neutral
Varity_R		0.80
gMVP		0.91
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs147472391; hg19: chr9-6534775;