rs386833571

Variant names:

• chr9-6534758-A-G
• rs386833571
• NM_000170.3:c.2869T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000170.3(GLDC):​c.2869T>C​(p.Ser957Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,455,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 1.67

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3	c.2869T>C	p.Ser957Pro	missense_variant	Exon 24 of 25	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.2869T>C	p.Ser957Pro	missense_variant	Exon 24 of 25	1	NM_000170.3	ENSP00000370737.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251212 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135780

Gnomad AFR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1455206 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 724442

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: 0.00000543

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycine encephalopathy Pathogenic:1 Uncertain:1

-

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with proline at codon 957 of the GLDC protein (p.Ser957Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. This variant is present in population databases (rs386833571, ExAC 0.003%). This missense change has been observed in individual(s) with glycine encephalopathy (PMID: 16601880; Invitae). ClinVar contains an entry for this variant (Variation ID: 56090). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Sep 24, 2024

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.2869T>C (p.Ser957Pro) 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 8e-06 in 251212 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2869T>C has been reported in the literature in an heterozygous individual affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) with the second allele change unknown (Conter_2006). These report(s) do not provide unequivocal conclusions about association of the variant with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 16601880). ClinVar contains an entry for this variant (Variation ID: 56090). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Jun 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.;.;.
Eigen	Benign	0.097
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.54	D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	2.9	M;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.0	D;.;.;.
REVEL	Uncertain	0.64
Sift	Benign	0.037	D;.;.;.
Sift4G	Uncertain	0.030	D;.;.;.
Polyphen		0.86	P;.;.;.
Vest4		0.72
MutPred		0.47		Loss of helix (P = 0.0093);.;.;.;
MVP		0.96
MPC		0.18
ClinPred		0.93	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.87
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

Other links and lift over

dbSNP: rs386833571; hg19: chr9-6534758; COSMIC: COSV58676601;