VCV000056062.7 - ClinVar

NM_000170.3(GLDC):c.2186del (p.Ala729fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000170.3(GLDC):c.2186del (p.Ala729fs)

Variation ID: 56062 Accession: VCV000056062.7

Type and length

Deletion, 1 bp

Location

Cytogenetic: 9p24.1 9: 6556169 (GRCh38) [ NCBI UCSC ] 9: 6556169 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 24, 2013	Feb 28, 2024	Sep 10, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000170.3:c.2186del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000161.2:p.Ala729fs	frameshift
NM_000170.2:c.2186delC
NC_000009.12:g.6556169del
NC_000009.11:g.6556169del
NG_016397.1:g.94524del
LRG_643:g.94524del

... more HGVS ... less HGVS

Protein change

A729fs

Other names

Canonical SPDI

NC_000009.12:6556168:G:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA263341 dbSNP: rs386833543 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GLDC		-	-	GRCh38 GRCh37	2431	2630

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Non-ketotic hyperglycinemia	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Sep 10, 2023	RCV000049471.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 08, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Non-ketotic hyperglycinemia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001519400.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Publications: PubMed (4) PubMed: 16601880‚ 26179960‚ 27362913‚ 31028937 Comment: Variant summary: GLDC c.2186delC (p.Ala729GlufsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: GLDC c.2186delC (p.Ala729GlufsX3) 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 was absent in 251416 control chromosomes in gnomAD v2.1.1. However, the variant allele was found at a frequency of 0.001096 in 912 control chromosomes within the Amish subpopulation in the newer gnomAD v3.1. c.2186delC has been reported in the literature in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (e.g. Conter_2006, 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). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Sep 10, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Non-ketotic hyperglycinemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000636375.4 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 16601880 Comment: This sequence change creates a premature translational stop signal (p.Ala729Glufs3) in the GLDC gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Ala729Glufs3) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 56062). This premature translational stop signal has been observed in individual(s) with glycine encephalopathy (PMID: 16601880). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). (less)
probable-pathogenic (-)	no assertion criteria provided Method: not provided	Non-ketotic hyperglycinemia Affected status: not provided Allele origin: not provided	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) Accession: SCV000081905.1 First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013 Comment: FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference	Comment: Converted during submission to Likely pathogenic.
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Non-ketotic hyperglycinemia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001457120.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Comment:

Variant summary: GLDC c.2186delC (p.Ala729GlufsX3) 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 was absent in 251416 control chromosomes in gnomAD v2.1.1. However, the variant allele was found at a frequency of 0.001096 in 912 control chromosomes within the Amish subpopulation in the newer gnomAD v3.1. c.2186delC has been reported in the literature in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (e.g. Conter_2006, 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). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Ala729Glufs*3) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 56062). This premature translational stop signal has been observed in individual(s) with glycine encephalopathy (PMID: 16601880). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Development of a Novel Next-Generation Sequencing Assay for Carrier Screening in Old Order Amish and Mennonite Populations of Pennsylvania.	Crowgey EL	The Journal of molecular diagnostics : JMD	2019	PMID: 31028937
The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT.	Coughlin CR 2nd	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27362913
Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia.	Swanson MA	Annals of neurology	2015	PMID: 26179960
Genetic heterogeneity of the GLDC gene in 28 unrelated patients with glycine encephalopathy.	Conter C	Journal of inherited metabolic disease	2006	PMID: 16601880

Text-mined citations for rs386833543 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000170.3(GLDC):c.2186del (p.Ala729fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs386833543 ...