NM_000170.3(GLDC):c.2033_2035del (p.Ala678del) AND Non-ketotic hyperglycinemia

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jun 16, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000674479.16

Allele description [Variation Report for NM_000170.3(GLDC):c.2033_2035del (p.Ala678del)]

NM_000170.3(GLDC):c.2033_2035del (p.Ala678del)

Gene:

GLDC:glycine decarboxylase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

9p24.1

Genomic location:

Preferred name:

NM_000170.3(GLDC):c.2033_2035del (p.Ala678del)

HGVS:

NC_000009.11:g.6558576_6558578del
NC_000009.12:g.6558577_6558579del
NG_016397.1:g.92115_92117del
NM_000170.3:c.2033_2035delMANE SELECT
NP_000161.2:p.Ala678del
NP_000161.2:p.Ala678del
LRG_643t1:c.2033_2035del
LRG_643:g.92115_92117del
LRG_643p1:p.Ala678del
NC_000009.11:g.6558576_6558578del
NC_000009.11:g.6558576_6558578delCTG
NC_000009.11:g.6558577_6558579del
NM_000170.2:c.2033_2035del
NM_000170.2:c.2033_2035delCAG
p.Ala678del

Protein change:

A678del

Links:

dbSNP: rs769625871

NCBI 1000 Genomes Browser:

rs769625871

Molecular consequence:

NM_000170.3:c.2033_2035del - inframe_deletion - [Sequence Ontology: SO:0001822]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000799822	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (May 8, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000966999	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Oct 9, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26179960, 24033266
SCV001410617	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 16, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26179960, 28492532
SCV001457122	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Sep 16, 2020)	germline	clinical testing

Help

Summary from all submissions

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

Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia.

Swanson MA, Coughlin CR Jr, Scharer GH, Szerlong HJ, Bjoraker KJ, Spector EB, Creadon-Swindell G, Mahieu V, Matthijs G, Hennermann JB, Applegarth DA, Toone JR, Tong S, Williams K, Van Hove JL.

Ann Neurol. 2015 Oct;78(4):606-18. doi: 10.1002/ana.24485. Epub 2015 Aug 10. Erratum in: Ann Neurol. 2016 Mar;79(3):505. doi: 10.1002/ana.24600.

PubMed [citation]

PMID:: 26179960
PMCID:: PMC4767401

See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000799822.1

#	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, SCV000966999.1

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

Description

The p.Ala678del variant in GLDC has been reported in one individual with glycine encephalopathy who carried a deletion of exons 3-21 in trans (Swanson 2015). It has also been identified in 1/111670 of European chromosomes by gnomAD (http:// gnomad.broadinstitute.org). This variant is a deletion of one amino acid at posi tion 678 and is not predicted to alter the protein reading-frame. In summary, al though additional studies are required to fully establish its clinical significa nce, the p.Ala678del variant is likely pathogenic. ACMG/AMP criteria applied: PM 2, PM3, PP4, PM4_Supporting.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001410617.5

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

Description

Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects GLDC function (PMID: 26179960). ClinVar contains an entry for this variant (Variation ID: 558242). This variant has been observed in individual(s) with glycine encephalopathy (PMID: 26179960). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs769625871, gnomAD 0.0009%). This variant, c.2033_2035del, results in the deletion of 1 amino acid(s) of the GLDC protein (p.Ala678del), but otherwise preserves the integrity of the reading frame.

#	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., SCV001457122.1

#	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: Sep 29, 2024

ClinVar

Relating variation to medicine