rs121964980

Positions:

chr9-6554768-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The ENST00000321612.8(GLDC):c.2216G>A(p.Arg739His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000292 in 1,612,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R739C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

GLDC
ENST00000321612.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.53

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 16 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in ENST00000321612.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-6554769-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1490298.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

PP5

Variant 9-6554768-C-T is Pathogenic according to our data. Variant chr9-6554768-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6554768-C-T is described in Lovd as [Pathogenic]. Variant chr9-6554768-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLDC	NM_000170.3 linkuse as main transcript	c.2216G>A	p.Arg739His	missense_variant	19/25	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8 linkuse as main transcript	c.2216G>A	p.Arg739His	missense_variant	19/25	1	NM_000170.3	ENSP00000370737	P1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000363

AC:

AN:

247686

Hom.:

AF XY:

0.0000374

AC XY:

AN XY:

133700

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000583

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000535

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1460010

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

726104

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0000722

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000638

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Non-ketotic hyperglycinemia

Pathogenic:5

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 739 of the GLDC protein (p.Arg739His). This variant is present in population databases (rs121964980, gnomAD 0.007%). This missense change has been observed in individual(s) with GLDC-related conditions (PMID: 15824356, 16450403, 17074608; Invitae). ClinVar contains an entry for this variant (Variation ID: 11990). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLDC protein function. Experimental studies have shown that this missense change affects GLDC function (PMID: 15824356). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 03, 2020	Variant summary: GLDC c.2216G>A (p.Arg739His) 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 3.6e-05 in 247686 control chromosomes. c.2216G>A has been reported in the literature in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (example, Dinopoulos_2005, Kure_2006, unpublished source from bioRxiv_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Dinopoulos_2005). The most pronounced variant effect results in <10% of normal GLDC enzyme activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 11, 2021	NM_000170.2(GLDC):c.2216G>A(R739H) is a missense variant classified as likely pathogenic in the context of glycine encephalopathy, GLDC-related. Please note that R739H may be associated with an attenuated form of glycine encephalopathy, GLDC-related. R739H has been observed in cases with relevant disease (PMID: 15824356, 16450403, 17074608, 27362913, 33977025, SSIEM_2005_(no PMID; abstract)). Functional assessments of this variant are available in the literature (PMID: 15824356). R739H has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000170.2(GLDC):c.2216G>A(R739H) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	GLDC: PM1, PM2, PM3, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2024	Published functional studies demonstrate that the R739H variant had decreased enzymatic activity (PMID: 15824356); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15824356, 16450403, 31589614, 30833958, Roa2023[Abstract], 33977025, 17074608) -

Glycine encephalopathy 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 12, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

D;.;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;.;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.5

D;.;.

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0080

D;.;.

Sift4G

Uncertain

0.0090

D;.;.

Polyphen

1.0

D;.;.

Vest4

0.97

MVP

1.0

MPC

0.34

ClinPred

0.99

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.91

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