rs758029533

Positions:

• chr9-6536104-A-G
• chr9-6536104-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000170.3(GLDC):​c.2798T>C​(p.Ile933Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I933F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 8.82

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a helix (size 21) in uniprot entity GCSP_HUMAN there are 5 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 chr9-6536105-T-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857
• PP5: Variant 9-6536104-A-G is Pathogenic according to our data. Variant chr9-6536104-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551679.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=2}. Variant chr9-6536104-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLDC	NM_000170.3	c.2798T>C	p.Ile933Thr	missense_variant	23/25	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.2798T>C	p.Ile933Thr	missense_variant	23/25	1	NM_000170.3	ENSP00000370737	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251392 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Non-ketotic hyperglycinemia Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 16, 2021	NM_000170.2(GLDC):c.2798T>C(I933T) is a missense variant classified as a variant of uncertain significance in the context of glycine encephalopathy, GLDC-related. I933T has been observed in cases with relevant disease (PMID: 27362913). Functional assessments of this variant are available in the literature (PMID: 28244183). I933T has been observed in population frequency databases (gnomAD: OTH 0.02%). In summary, there is insufficient evidence to classify NM_000170.2(GLDC):c.2798T>C(I933T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 933 of the GLDC protein (p.Ile933Thr). This variant is present in population databases (rs758029533, gnomAD 0.006%). This missense change has been observed in individual(s) with glycine encephalopathy (PMID: 26179960, 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: 551679). 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. This variant disrupts the p.Ile933 amino acid residue in GLDC. Other variant(s) that disrupt this residue have been observed in individuals with GLDC-related conditions (PMID: 27362913), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 19, 2021	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2022	Published functional studies suggest decreased expression and GCS P-protein exchange activity (Bravo-Alonso et al., 2017); 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: 26179960, 28244183, 27362913) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.5	H;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.3	D;.;.;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.
Polyphen		1.0	D;.;.;.
Vest4		0.94
MutPred		0.54		Loss of helix (P = 0.0376);.;.;.;
MVP		0.96
MPC		0.26
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.78
gMVP		0.88

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: rs758029533; hg19: chr9-6536104;