VCV000225378.39 - ClinVar

NM_000170.3(GLDC):c.1229G>A (p.Arg410Lys)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(7); Likely benign(2)

10 out of 11 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000170.3(GLDC):c.1229G>A (p.Arg410Lys)

Variation ID: 225378 Accession: VCV000225378.39

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9p24.1 9: 6595046 (GRCh38) [ NCBI UCSC ] 9: 6595046 (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	Oct 2, 2016	Jun 22, 2025	Mar 1, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000170.3:c.1229G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000161.2:p.Arg410Lys	missense
NC_000009.12:g.6595046C>T
NC_000009.11:g.6595046C>T
NG_016397.1:g.55647G>A
LRG_643:g.55647G>A
LRG_643t1:c.1229G>A	LRG_643p1:p.Arg410Lys

... more HGVS ... less HGVS

Protein change

R410K

Other names

Canonical SPDI

NC_000009.12:6595045:C:T

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.

0.00899 (T)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046

The Genome Aggregation Database (gnomAD) 0.00234

The Genome Aggregation Database (gnomAD) 0.00257

Trans-Omics for Precision Medicine (TOPMed) 0.00475

1000 Genomes Project 0.00899

1000 Genomes Project 30x 0.00984

Links

ClinGen: CA4980799 dbSNP: rs144090917 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		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	2529	2729

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.
Glycine encephalopathy	Conflicting classifications of pathogenicity (6)	criteria provided, conflicting classifications	Feb 4, 2025	RCV000299139.26
not specified	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jul 2, 2024	RCV000243554.10
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Mar 1, 2025	RCV001706208.16

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.
Uncertain significance (Mar 18, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: reference population	Glycine encephalopathy 1 Affected status: unknown Allele origin: germline	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center Accession: SCV000267344.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (1) PubMed: 12126939 Number of individuals with the variant: 1 Age: 40-69 years Ethnicity/Population group: East Asian Geographic origin: South Korean

Benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000302840.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016

Likely benign (Apr 28, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Glycine encephalopathy 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000480516.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 12126939 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)

Benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Glycine encephalopathy 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435262.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Publications: PubMed (1) PubMed: 12126939 Comment: The homozygous p.Arg410Lys variant in GLDC has been identified in an individual with non-ketotic hyperglycinaemia (PMID: 12126939), but has also been identified in >2% of … (more) The homozygous p.Arg410Lys variant in GLDC has been identified in an individual with non-ketotic hyperglycinaemia (PMID: 12126939), but has also been identified in >2% of Latino chromosomes and 8 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive non-ketotic hyperglycinaemia. (less) Platform type: WES

Benign (Nov 20, 2018) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001889207.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Comment: This variant is associated with the following publications: (PMID: 29153744, 27535533, 27362913, 12126939)

Likely benign (Dec 10, 2021) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002050865.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022

Benign (Jul 13, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Glycine encephalopathy 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001137744.2 First in ClinVar: Jan 09, 2020 Last updated: Jul 16, 2023

benign (Jul 02, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001475870.2 First in ClinVar: Jan 26, 2021 Last updated: Jan 19, 2025	Publications: PubMed (4) PubMed: 27535533‚ 12126939‚ 27362913‚ 29153744

Benign (Feb 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Glycine encephalopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000636350.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 25, 2025

Benign (Mar 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004161867.15 First in ClinVar: Nov 20, 2023 Last updated: Jun 22, 2025	Comment: GLDC: BS1, BS2 Number of individuals with the variant: 5

Benign (Jan 09, 2020) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Non-ketotic hyperglycinemia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001462765.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

The homozygous p.Arg410Lys variant in GLDC has been identified in an individual with non-ketotic hyperglycinaemia (PMID: 12126939), but has also been identified in >2% of Latino chromosomes and 8 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive non-ketotic hyperglycinaemia.

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
Molecular and functional characterization of familial chylomicronemia syndrome.	Teramoto R	Atherosclerosis	2018	PMID: 29153744
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
Analysis of protein-coding genetic variation in 60,706 humans.	Lek M	Nature	2016	PMID: 27535533
Novel mutations in the P-protein (glycine decarboxylase) gene in patients with glycine encephalopathy (non-ketotic hyperglycinemia).	Toone JR	Molecular genetics and metabolism	2002	PMID: 12126939

Text-mined citations for rs144090917 ...

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 Jun 22, 2025

ClinVar Genomic variation as it relates to human health

NM_000170.3(GLDC):c.1229G>A (p.Arg410Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs144090917 ...