9-6556173-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000170.3(GLDC):c.2182G>A(p.Gly728Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G728E) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GLDC
NM_000170.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.54

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 22 ACMG points.

PS1

Transcript NM_000170.3 (GLDC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM1

In a helix (size 5) in uniprot entity GCSP_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000170.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-6556172-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

PP5

Variant 9-6556173-C-T is Pathogenic according to our data. Variant chr9-6556173-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 580932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6556173-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3 link	c.2182G>A	p.Gly728Arg	missense_variant	Exon 18 of 25	ENST00000321612.8	NP_000161.2	P23378

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8 link	c.2182G>A	p.Gly728Arg	missense_variant	Exon 18 of 25	1	NM_000170.3	ENSP00000370737.4		P23378

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251430

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135890

show subpopulations

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460918

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726790

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycine encephalopathy

Pathogenic:2

May 15, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GLDC c.2182G>A (p.Gly728Arg) results in a non-conservative amino acid change located in the Aromatic amino acid beta-eliminating lyase/threonine aldolase domain (IPR001597) of 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 4e-06 in 251430 control chromosomes. c.2182G>A (and a different variant with the same protein effect, c.2182G>C) have been reported in the literature in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (example, Coughlin_2017, Coughlin_2018 [erratum], Kure_2006, Ning_2021, Shellhaas_2017, Swanson_2022, Trujillano_2017). Further, a different missense variant at the same codon p.Gly728Glu has been classified as pathogenic in ClinVar (ID 2735246). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27362913, 29300369, 16450403, 34587689, 28733343, 35357708, 28116331). ClinVar contains an entry for this variant (Variation ID: 580932). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 728 of the GLDC protein (p.Gly728Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of glycine encephalopathy (PMID: 27362913; Invitae). ClinVar contains an entry for this variant (Variation ID: 580932). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly728 amino acid residue in GLDC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26179960, 27362913). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Glycine encephalopathy 1

Pathogenic:1

May 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

H;.;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.7

D;.;.

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0

D;.;.

Polyphen

1.0

D;.;.

Vest4

0.99

MutPred

0.95

Gain of methylation at G728 (P = 0.1386);.;.;

MVP

0.98

MPC

0.34

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.95

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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