NM_000170.3(GLDC):c.128del (p.Asp43fs) AND Non-ketotic hyperglycinemia

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jul 27, 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:: RCV000667354.14

Allele description [Variation Report for NM_000170.3(GLDC):c.128del (p.Asp43fs)]

NM_000170.3(GLDC):c.128del (p.Asp43fs)

Gene:

GLDC:glycine decarboxylase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

9p24.1

Genomic location:

Preferred name:

NM_000170.3(GLDC):c.128del (p.Asp43fs)

HGVS:

NC_000009.12:g.6645372del
NG_016397.1:g.5321del
NM_000170.3:c.128delMANE SELECT
NP_000161.2:p.Asp43fs
NP_000161.2:p.Asp43fs
LRG_643t1:c.128del
LRG_643:g.5321del
LRG_643p1:p.Asp43fs
NC_000009.11:g.6645372del
NC_000009.11:g.6645372delT
NM_000170.2:c.128del
NM_000170.2:c.128delA
p.Asp43AlafsX48

Protein change:

D43fs

Links:

dbSNP: rs1251443902

NCBI 1000 Genomes Browser:

rs1251443902

Molecular consequence:

NM_000170.3:c.128del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000791788	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (May 23, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000966894	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Feb 7, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26179960, 24033266
SCV001385089	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16601880, 30609409, 28492532
SCV001519600	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 8, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26179960, 27362913, 30609409, 31028937 Citation Link,
SCV002078199	Natera, Inc.	no assertion criteria provided	Pathogenic (Apr 5, 2021)	germline	clinical testing

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	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Genetic heterogeneity of the GLDC gene in 28 unrelated patients with glycine encephalopathy.

Conter C, Rolland MO, Cheillan D, Bonnet V, Maire I, Froissart R.

J Inherit Metab Dis. 2006 Feb;29(1):135-42.

PubMed [citation]

PMID:: 16601880

See all PubMed Citations (7)

Details of each submission

From Counsyl, SCV000791788.1

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

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000966894.1

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

Description

The p.Asp43AlafsX48 (NM_000170.2 c.128delA) variant in GLDC has been previously reported in 1 compound heterozygous individual with glycine encephalopathy (Swan son 2015), and was absent from large population studies. This variant is predict ed to cause a frameshift, which alters the protein?s amino acid sequence beginni ng at position 43 and leads to a premature termination codon 48 amino acids down stream. This alteration is then predicted to lead to a truncated or absent prote in. Biallelic loss of function of the GLDC gene is associated with glycine encep halopathy. In summary, the p.Asp43AlafsX48 variant meets our criteria to be clas sified as pathogenic for glycine encephalopathy in an autosomal recessive manner based on its occurrence in trans with another pathogenic variant in an affected individual and its predicted impact on the protein.

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

From Invitae, SCV001385089.5

#	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 creates a premature translational stop signal (p.Asp43Alafs*48) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with encephalopathy (PMID: 30609409). ClinVar contains an entry for this variant (Variation ID: 552137). 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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001519600.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: GLDC c.128delA (p.Asp43AlafsX48) 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 1.3e-05 in 150762 control chromosomes (gnomAD v3.1). c.128delA has been reported in the literature in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (e.g. Swanson_2015, Coughlin_2017) and is included as a pathogenic variant in targeted testing panels for Amish communities (e.g. Crowgey_2019, Clinic for Special Children). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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

From Natera, Inc., SCV002078199.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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: Feb 20, 2024

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