VCV003363148.1 - ClinVar

NM_016128.4(COPG1):c.1954A>G (p.Lys652Glu)

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.

(1)

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

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_016128.4(COPG1):c.1954A>G (p.Lys652Glu)

Variation ID: 3363148 Accession: VCV003363148.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q21.3 3: 129271877 (GRCh38) [ NCBI UCSC ] 3: 128990720 (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 27, 2024	Oct 26, 2024	Oct 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_016128.4:c.1954A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_057212.1:p.Lys652Glu	missense
NC_000003.12:g.129271877A>G
NC_000003.11:g.128990720A>G

Protein change

Other names

K652E

Canonical SPDI

NC_000003.12:129271876:A: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.

Links

OMIM: 615525.0001 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.
COPG1		-	-	GRCh38 GRCh37	75	89

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.
IMMUNODEFICIENCY 128	Pathogenic (1)	no assertion criteria provided	Oct 18, 2024	RCV004765435.1

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 (Oct 18, 2024)	no assertion criteria provided Method: literature only	IMMUNODEFICIENCY 128 (1 family) Affected status: not provided Allele origin: germline	OMIM Accession: SCV005375274.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Publications: PubMed (1) PubMed: 33529166 Comment on evidence: In 5 sibs, born of consanguineous Omani parents, with immunodeficiency-128 (IMD128; 620983), Bainter et al. (2021) identified a homozygous c.1954A-G transition in the COPG1 gene, … (more) In 5 sibs, born of consanguineous Omani parents, with immunodeficiency-128 (IMD128; 620983), Bainter et al. (2021) identified a homozygous c.1954A-G transition in the COPG1 gene, resulting in a lys652-to-glu (K652E) substitution at a highly conserved residue at the N-terminal end of the appendage domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was heterozygous in the unaffected parents. It was not present in the 1000 Genomes Project or ExAC databases. Immunoblot analysis of patient fibroblasts showed expression levels of the mutant protein comparable to controls, and coimmunoprecipitation studies suggested that mutant COPG1 integrated normally into the COPI complex. Patient fibroblasts showed impaired retrograde COPI transport compared to controls, as evidenced by increased KDELR1 (131235) localization to the Golgi; direct binding of the mutant COPG1 coatomer to KDELR1 was disrupted by the K652E mutation. Binding to ARFGAP1 (608377) was retained and may have compensated for the defect. Vesicle formation was unaffected. Similar defects were observed in embryonic fibroblasts from mutant mice expressing the K652E mutation (see ANIMAL MODEL). Overall, the findings suggested that impaired retrieval of KDEL-bearing chaperones to the ER causes exaggerated ER stress in activated B and T cells. (less)

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Combined immunodeficiency due to a mutation in the γ1 subunit of the coat protein I complex.	Bainter W	The Journal of clinical investigation	2021	PMID: 33529166

Text-mined citations for this variant ...

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_016128.4(COPG1):c.1954A>G (p.Lys652Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...