rs1288008254

Positions:

• chr9-6533118-G-A
• chr9-6533118-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000170.3(GLDC):​c.2962C>T​(p.Arg988Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,056 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. R988Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 2.35

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-6533117-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 9-6533118-G-A is Pathogenic according to our data. Variant chr9-6533118-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554524.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}. Variant chr9-6533118-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLDC	NM_000170.3	c.2962C>T	p.Arg988Trp	missense_variant	25/25	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.2962C>T	p.Arg988Trp	missense_variant	25/25	1	NM_000170.3	ENSP00000370737.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460056 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726532

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000930 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycine encephalopathy 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 06, 2024	- -

Glycine encephalopathy Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 13, 2021	For these reasons, this variant has been classified as Pathogenic. 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. This variant has been observed in individual(s) with glycine encephalopathy (PMID: 27362913). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 554524). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 988 of the GLDC protein (p.Arg988Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 24, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.1	H;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.2	D;.;.;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.
Polyphen		1.0	D;.;.;.
Vest4		0.93
MutPred		0.86		Gain of glycosylation at T985 (P = 0.0502);.;.;.;
MVP		0.98
MPC		0.32
ClinPred		1.0	D
GERP RS		3.1
Varity_R		0.85
gMVP		0.98

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: rs1288008254; hg19: chr9-6533118;