NM_000170.3(GLDC):c.847G>C (p.Ala283Pro) AND Non-ketotic hyperglycinemia

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 26, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000049515.6

Allele description [Variation Report for NM_000170.3(GLDC):c.847G>C (p.Ala283Pro)]

NM_000170.3(GLDC):c.847G>C (p.Ala283Pro)

Gene:

GLDC:glycine decarboxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9p24.1

Genomic location:

Preferred name:

NM_000170.3(GLDC):c.847G>C (p.Ala283Pro)

HGVS:

NC_000009.12:g.6605145C>G
NG_016397.1:g.45548G>C
NM_000170.3:c.847G>CMANE SELECT
NP_000161.2:p.Ala283Pro
NP_000161.2:p.Ala283Pro
LRG_643t1:c.847G>C
LRG_643:g.45548G>C
LRG_643p1:p.Ala283Pro
NC_000009.11:g.6605145C>G
NM_000170.2:c.847G>C
P23378:p.Ala283Pro

Protein change:

A283P

Links:

UniProtKB: P23378#VAR_016849; dbSNP: rs386833589

NCBI 1000 Genomes Browser:

rs386833589

Molecular consequence:

NM_000170.3:c.847G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Non-ketotic hyperglycinemia
Synonyms:: Glycine encephalopathy; Nonketotic hyperglycinemia
Identifiers:: MONDO: MONDO:0011612; MedGen: C0751748; Orphanet: 407; OMIM: PS605899; Human Phenotype Ontology: HP:0008288

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Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase family protein [Arabidopsis thaliana]
gi|240256429|ref|NP_199891.4|

Protein
Priestia aryabhattai strain NWPZ-6 16S ribosomal RNA gene, partial sequence
Priestia aryabhattai strain NWPZ-6 16S ribosomal RNA gene, partial sequence
gi|1820466557|gb|MT184818.1|

Nucleotide
Curtobacterium sp. strain MAIDO-R16b-9 16S ribosomal RNA gene, partial sequence
Curtobacterium sp. strain MAIDO-R16b-9 16S ribosomal RNA gene, partial sequence
gi|1989819652|gb|MW631980.1|

Nucleotide
Psychrobacillus psychrodurans strain CSBB_294 16S ribosomal RNA gene, partial se...
Psychrobacillus psychrodurans strain CSBB_294 16S ribosomal RNA gene, partial sequence
gi|1908372877|gb|MW033762.1|

Nucleotide
Kocuria sp. strain Can_S17 16S ribosomal RNA gene, partial sequence
Kocuria sp. strain Can_S17 16S ribosomal RNA gene, partial sequence
gi|2269694642|gb|ON965346.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000081951	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	no assertion criteria provided	probable-pathogenic	not provided	not provided	PubMed (1) [See all records that cite this PMID]
SCV000797996	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Feb 23, 2018)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26179960, 27362913 Citation Link,
SCV001591330	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 26, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27362913, 26179960, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000081951

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

no assertion criteria provided

probable-pathogenic

not provided

PubMed (1)
[See all records that cite this PMID]

SCV000797996

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Feb 23, 2018)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001591330

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 26, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Description

FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference: SCV000081951

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel mutations in the P-protein (glycine decarboxylase) gene in patients with glycine encephalopathy (non-ketotic hyperglycinemia).

Toone JR, Applegarth DA, Kure S, Coulter-Mackie MB, Sazegar P, Kojima K, Ichinohe A.

Mol Genet Metab. 2002 Jul;76(3):243-9.

PubMed [citation]

PMID:: 12126939

The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT.

Coughlin CR 2nd, Swanson MA, Kronquist K, Acquaviva C, Hutchin T, Rodríguez-Pombo P, Väisänen ML, Spector E, Creadon-Swindell G, Brás-Goldberg AM, Rahikkala E, Moilanen JS, Mahieu V, Matthijs G, Bravo-Alonso I, Pérez-Cerdá C, Ugarte M, Vianey-Saban C, Scharer GH, Van Hove JL.

Genet Med. 2017 Jan;19(1):104-111. doi: 10.1038/gim.2016.74. Epub 2016 Jun 30. Erratum in: Genet Med. 2018 Sep;20(9):1098. doi: 10.1038/gim.2017.232.

PubMed [citation]

PMID:: 27362913

See all PubMed Citations (4)

Details of each submission

From Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), SCV000081951.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	PubMed (1)

Description

Converted during submission to Likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not provided	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000797996.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001591330.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 283 of the GLDC protein (p.Ala283Pro). This variant is present in population databases (rs386833589, gnomAD 0.0009%). This missense change has been observed in individual(s) with glycine encephalopathy (PMID: 26179960, 27362913). ClinVar contains an entry for this variant (Variation ID: 56106). 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%. Experimental studies have shown that this missense change affects GLDC function (PMID: 26179960). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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