rs386833518
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000170.3(GLDC):βc.1054delβ(p.Thr352GlnfsTer65) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000931 in 1,611,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000020 ( 0 hom., cov: 32)
Exomes π: 0.0000082 ( 0 hom. )
Consequence
GLDC
NM_000170.3 frameshift
NM_000170.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.70
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-6604591-GT-G is Pathogenic according to our data. Variant chr9-6604591-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6604591-GT-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLDC | NM_000170.3 | c.1054del | p.Thr352GlnfsTer65 | frameshift_variant | 7/25 | ENST00000321612.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLDC | ENST00000321612.8 | c.1054del | p.Thr352GlnfsTer65 | frameshift_variant | 7/25 | 1 | NM_000170.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152116Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251262Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135804
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GnomAD4 exome AF: 0.00000822 AC: 12AN: 1459042Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5AN XY: 725906
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74304
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Non-ketotic hyperglycinemia Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 14, 2022 | This premature translational stop signal has been observed in individual(s) with non-ketotic hyperglycinemia (PMID: 17361008). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 56037). This variant is present in population databases (rs386833518, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Thr352Glnfs*65) in the GLDC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLDC are known to be pathogenic (PMID: 16601880). - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 06, 2019 | Variant summary: GLDC c.1054delA (p.Thr352GlnfsX65) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251262 control chromosomes. c.1054delA has been reported in the literature in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (Toone_2002, Kanno_2007, Coughlin_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 03, 2016 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 21, 2021 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17361008, 30385710, 28759667, 12126939) - |
GLDC-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 29, 2022 | The GLDC c.1054delA variant is predicted to result in a frameshift and premature protein termination (p.Thr352Glnfs*65). This variant has been reported in patients with autosomal recessive glycine encephalopathy (Toone et al. 2002. PubMed ID: 12126939; Family P41, Kanno et al. 2007. PubMed ID: 17361008). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-6604591-GT-G). Frameshift variants in GLDC are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
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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