rs759133707
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_000170.3(GLDC):c.1145G>A(p.Cys382Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,450,534 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
GLDC
NM_000170.3 missense
NM_000170.3 missense
Scores
17
1
1
Clinical Significance
Conservation
PhyloP100: 7.39
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
Variant 9-6602119-C-T is Pathogenic according to our data. Variant chr9-6602119-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 531778.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-6602119-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GLDC | NM_000170.3 | c.1145G>A | p.Cys382Tyr | missense_variant | 8/25 | ENST00000321612.8 | NP_000161.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GLDC | ENST00000321612.8 | c.1145G>A | p.Cys382Tyr | missense_variant | 8/25 | 1 | NM_000170.3 | ENSP00000370737.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251440Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135892
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GnomAD4 exome AF: 0.00000414 AC: 6AN: 1450534Hom.: 0 Cov.: 29 AF XY: 0.00000415 AC XY: 3AN XY: 722432
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GnomAD4 genome Cov.: 32
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32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Non-ketotic hyperglycinemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 10, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 382 of the GLDC protein (p.Cys382Tyr). This variant is present in population databases (rs759133707, gnomAD 0.002%). 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: 531778). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;.
Polyphen
D;.
Vest4
MutPred
Gain of catalytic residue at I381 (P = 0.0265);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at