VCV000127098.10 - ClinVar

NM_006302.3(MOGS):c.370C>T (p.Gln124Ter)

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.

(6)

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_006302.3(MOGS):c.370C>T (p.Gln124Ter)

Variation ID: 127098 Accession: VCV000127098.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p13.1 2: 74464705 (GRCh38) [ NCBI UCSC ] 2: 74691832 (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 2, 2015	Feb 14, 2024	Aug 10, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006302.3:c.370C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006293.2:p.Gln124Ter	nonsense
NM_001146158.2:c.52C>T	NP_001139630.1:p.Gln18Ter	nonsense
NC_000002.12:g.74464705G>A
NC_000002.11:g.74691832G>A
NG_008922.1:g.5706C>T
LRG_1226:g.5706C>T
LRG_1226t1:c.370C>T	LRG_1226p1:p.Gln124Ter

... more HGVS ... less HGVS

Protein change

Q124*, Q18*

Other names

MOGS, GLN124TER (rs587777323)

Canonical SPDI

NC_000002.12:74464704:G:A

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.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00005

The Genome Aggregation Database (gnomAD) 0.00007

Links

ClinGen: CA269769 OMIM: 601336.0003 dbSNP: rs587777323 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.
MOGS		-	-	GRCh38 GRCh37	481	544

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.
MOGS-congenital disorder of glycosylation	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Aug 10, 2023	RCV000114956.15
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 7, 2020	RCV001588924.3

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 (Aug 10, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	MOGS-congenital disorder of glycosylation Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000959388.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 24716661‚ 26805780 Comment: This sequence change creates a premature translational stop signal (p.Gln124) in the MOGS gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Gln124) in the MOGS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MOGS are known to be pathogenic (PMID: 24716661, 26805780). This variant is present in population databases (rs587777323, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with MOGS-congenital disorder of glycosylation (PMID: 26805780). ClinVar contains an entry for this variant (Variation ID: 127098). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 28, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MOGS-congenital disorder of glycosylation Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001521849.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Jan 12, 2015)	criteria provided, single submitter (Courtagen Life Sciences Classifications) Method: clinical testing	Congenital disorder of glycosylation, type IIb Affected status: unknown Allele origin: germline	Courtagen Diagnostics Laboratory, Courtagen Life Sciences Accession: SCV000236530.2 First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015
Pathogenic (Jul 07, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001823586.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Comment: Nonsense variant predicted to result in protein truncation [or nonsense mediated decay] in a gene for which loss-of-function is a known mechanism of disease; Not … (more) Nonsense variant predicted to result in protein truncation [or nonsense mediated decay] in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26805780, 24716661, 29431110) (less)
Pathogenic (Jan 04, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MOGS-congenital disorder of glycosylation Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002803156.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Apr 24, 2014)	no assertion criteria provided Method: literature only	CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIb Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000148866.5 First in ClinVar: Apr 27, 2014 Last updated: Apr 21, 2017	Publications: PubMed (2) PubMed: 24716661‚ 26805780 Comment on evidence: In 2 sibs with congenital disorder of glycosylation type IIb (CDG2B; 606056), Sadat et al. (2014) identified compound heterozygous mutations in the MOGS gene. The … (more) In 2 sibs with congenital disorder of glycosylation type IIb (CDG2B; 606056), Sadat et al. (2014) identified compound heterozygous mutations in the MOGS gene. The maternal allele carried a c.370C-T transition, predicted to result in a gln124-to-ter (Q124X) substitution; the mutation resulted in nonsense-mediated mRNA decay. The paternal allele had 2 mutations: a c.65C-A transversion, predicted to result in an ala22-to-glu (A22E) substitution, and a c.329G-A transition, predicted to result in an arg110-to-his (R110H) substitution (601336.0004). The c.65C-A mutation affected splicing and resulted in nonsense-mediated mRNA decay, and the R110H mutant protein was rapidly degraded by the proteasome. Immunoblot analysis of patient cells showed lack of detectable MOGS protein, consistent with a loss of function. The patients had global developmental delay, hypotonia, seizures, dysmorphic features, and hypogammaglobulinemia. Kane et al. (2016) found that fibroblasts and blood derived from the sibs reported by Sadat et al. (2014) had increased amounts of nonparental genotypes surrounding the inherited variants. Detailed analysis indicated that there were some somatic genotypes with the wildtype allele. These findings suggested that reciprocal mitotic recombination can generate wildtype alleles in somatic cells, which may contribute to the survival and the variable expressivity seen in individuals with compound heterozygous mutations. (less)

Comment:

This sequence change creates a premature translational stop signal (p.Gln124*) in the MOGS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MOGS are known to be pathogenic (PMID: 24716661, 26805780). This variant is present in population databases (rs587777323, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with MOGS-congenital disorder of glycosylation (PMID: 26805780). ClinVar contains an entry for this variant (Variation ID: 127098). For these reasons, this variant has been classified as Pathogenic.

Comment:

Nonsense variant predicted to result in protein truncation [or nonsense mediated decay] in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26805780, 24716661, 29431110)

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
Mitotic Intragenic Recombination: A Mechanism of Survival for Several Congenital Disorders of Glycosylation.	Kane MS	American journal of human genetics	2016	PMID: 26805780
Glycosylation, hypogammaglobulinemia, and resistance to viral infections.	Sadat MA	The New England journal of medicine	2014	PMID: 24716661

Text-mined citations for rs587777323 ...

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_006302.3(MOGS):c.370C>T (p.Gln124Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587777323 ...