VCV000199254.13 - ClinVar

NM_004371.4(COPA):c.698G>A (p.Arg233His)

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_004371.4(COPA):c.698G>A (p.Arg233His)

Variation ID: 199254 Accession: VCV000199254.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q23.2 1: 160323439 (GRCh38) [ NCBI UCSC ] 1: 160293229 (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	Jun 29, 2015	Feb 14, 2024	Dec 10, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004371.4:c.698G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004362.2:p.Arg233His	missense
NM_001098398.2:c.698G>A	NP_001091868.1:p.Arg233His	missense
NC_000001.11:g.160323439C>T
NC_000001.10:g.160293229C>T
NG_050927.1:g.25126G>A
LRG_1336:g.25126G>A
LRG_1336t1:c.698G>A	LRG_1336p1:p.Arg233His
	P53621:p.Arg233His

... more HGVS ... less HGVS

Protein change

R233H

Other names

Canonical SPDI

NC_000001.11:160323438: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.

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: CA334830 UniProtKB: P53621#VAR_073845 OMIM: 601924.0001 dbSNP: rs794727993 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.
COPA		-	-	GRCh38 GRCh37	731	744

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.
Autoimmune interstitial lung disease-arthritis syndrome	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Dec 10, 2023	RCV000180776.15
See cases	Pathogenic (1)	criteria provided, single submitter	Dec 21, 2022	RCV003156081.1

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 (Apr 20, 2015)	criteria provided, single submitter (Watkin et al. (Nat Genet 2015)) Method: research	Autoimmune interstitial lung disease-arthritis syndrome (Autosomal dominant inheritance) Affected status: no, yes Allele origin: inherited	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine Accession: SCV000256756.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (1) PubMed: 25894502 Comment: Segregates with the phenotype in two affected families. One family showed incomplete penetrance, with one unaffected carrier over four generations. Observation 1: Number of individuals with the variant: 8 Family history: yes Observation 2: Number of individuals with the variant: 1 Family history: yes
Pathogenic (Dec 10, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autoimmune interstitial lung disease-arthritis syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000774975.8 First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 28492532‚ 25894502 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 233 of the COPA protein (p.Arg233His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 233 of the COPA protein (p.Arg233His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autoimmune-mediated lung disease and arthritis (PMID: 25894502). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 199254). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COPA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects COPA function (PMID: 25894502). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autoimmune interstitial lung, joint, and kidney disease (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital Accession: SCV000930528.1 First in ClinVar: Aug 04, 2019 Last updated: Aug 04, 2019	Comment: identified in different affected members of same family
Pathogenic (May 07, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autoimmune interstitial lung disease-arthritis syndrome Affected status: yes Allele origin: paternal	Baylor Genetics Accession: SCV001530127.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Publications: PubMed (2) PubMed: 25894502‚ 27577878 Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing in multiple individuals … (more) This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing in multiple individuals from two unrelated families with autoimmune disease and functional studies showed that this mutation causes increased ER stress [PMID 25894502, 27577878] (less)
Pathogenic (Dec 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: inherited	Center for Personalized Medicine, Children's Hospital Los Angeles Accession: SCV003845270.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023	Clinical Features: Arthropathy (present) , Reduced circulating complement concentration (present) , Immunodeficiency (present) , Abnormal pulmonary interstitial morphology (present) , Rheumatoid factor positive (present) , Short stature … (more) Arthropathy (present) , Reduced circulating complement concentration (present) , Immunodeficiency (present) , Abnormal pulmonary interstitial morphology (present) , Rheumatoid factor positive (present) , Short stature (present) (less)

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 233 of the COPA protein (p.Arg233His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autoimmune-mediated lung disease and arthritis (PMID: 25894502). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 199254). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COPA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects COPA function (PMID: 25894502). For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing in multiple individuals from two unrelated families with autoimmune disease and functional studies showed that this mutation causes increased ER stress [PMID 25894502, 27577878]

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
Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.	Stray-Pedersen A	The Journal of allergy and clinical immunology	2017	PMID: 27577878
COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis.	Watkin LB	Nature genetics	2015	PMID: 25894502

Text-mined citations for rs794727993 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_004371.4(COPA):c.698G>A (p.Arg233His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs794727993 ...