rs121964980

chr9-6554768-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000170.3(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. 12/20 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 NM_000170.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.53

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 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 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 chr9-6554769-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	UniProt
GLDC	NM_000170.3	c.2216G>A	p.Arg739His	missense_variant	19/25	ENST00000321612.8

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152204 Hom.: 0 Cov.: 33

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: 9 AN: 247686 Hom.: 0 AF XY: 0.0000374 AC XY: 5 AN XY: 133700

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: 38 AN: 1460010 Hom.: 0 Cov.: 31 AF XY: 0.0000207 AC XY: 15 AN XY: 726104

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: 9 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74490

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.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Non-ketotic hyperglycinemia Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 12, 2005	- -
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. -
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	Baylor Genetics	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 18, 2022

Published functional studies demonstrate that the R739H variant had decreased enzymatic activity (Dinopoulos et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15824356, 17074608, 16450403, 31589614, 30833958, 33977025) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.82	D
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	D
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

Other links and lift over

dbSNP: rs121964980; hg19: chr9-6554768; COSMIC: COSV58676016; COSMIC: COSV58676016;