NM_004371.4(COPA):c.721G>A (p.Glu241Lys) AND Autoimmune interstitial lung disease-arthritis syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 16, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000180778.13

Allele description [Variation Report for NM_004371.4(COPA):c.721G>A (p.Glu241Lys)]

NM_004371.4(COPA):c.721G>A (p.Glu241Lys)

Gene:

COPA:COPI coat complex subunit alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q23.2

Genomic location:

Preferred name:

NM_004371.4(COPA):c.721G>A (p.Glu241Lys)

HGVS:

NC_000001.11:g.160314111C>T
NG_050927.1:g.34454G>A
NM_001098398.2:c.721G>A
NM_004371.4:c.721G>AMANE SELECT
NP_001091868.1:p.Glu241Lys
NP_004362.2:p.Glu241Lys
LRG_1336t1:c.721G>A
LRG_1336:g.34454G>A
LRG_1336p1:p.Glu241Lys
NC_000001.10:g.160283901C>T
NM_001098398.1:c.721G>A
NM_004371.3:c.721G>A
P53621:p.Glu241Lys

Protein change:

E241K; GLU241LYS

Links:

UniProtKB: P53621#VAR_073846; OMIM: 601924.0003; dbSNP: rs794727995

NCBI 1000 Genomes Browser:

rs794727995

Molecular consequence:

NM_001098398.2:c.721G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004371.4:c.721G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Autoimmune interstitial lung disease-arthritis syndrome
Synonyms:: Autoimmune interstitial lung, joint, and kidney disease
Identifiers:: MONDO: MONDO:0014629; MedGen: C5243948; Orphanet: 444092; OMIM: 616414

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000233266	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 2015)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000256757	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	criteria provided, single submitter (Watkin et al. (Nat Genet 2015))	Pathogenic (Apr 20, 2015)	inherited	research	PubMed (1) [See all records that cite this PMID]
SCV001395665	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 7, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29137621, 25894502, 28492532
SCV003807015	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 16, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	5	1	not provided	not provided	yes	research
not provided	inherited	no	3	not provided	not provided	not provided	yes	research

Citations

PubMed

COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA.

Jensson BO, Hansdottir S, Arnadottir GA, Sulem G, Kristjansson RP, Oddsson A, Benonisdottir S, Jonsson H, Helgason A, Saemundsdottir J, Magnusson OT, Masson G, Thorisson GA, Jonasdottir A, Jonasdottir A, Sigurdsson A, Jonsdottir I, Petursdottir V, Kristinsson JR, Gudbjartsson DF, Thorsteinsdottir U, Arngrimsson R, et al.

BMC Med Genet. 2017 Nov 14;18(1):129. doi: 10.1186/s12881-017-0490-8.

PubMed [citation]

PMID:: 29137621
PMCID:: PMC5686906

COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis.

Watkin LB, Jessen B, Wiszniewski W, Vece TJ, Jan M, Sha Y, Thamsen M, Santos-Cortez RL, Lee K, Gambin T, Forbes LR, Law CS, Stray-Pedersen A, Cheng MH, Mace EM, Anderson MS, Liu D, Tang LF, Nicholas SK, Nahmod K, Makedonas G, Canter DL, et al.

Nat Genet. 2015 Jun;47(6):654-60. doi: 10.1038/ng.3279. Epub 2015 Apr 20.

PubMed [citation]

PMID:: 25894502
PMCID:: PMC4513663

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000233266.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In affected members of a large multigeneration family (family C) with autoimmune interstitial lung, joint, and kidney disease (AILJK; 616414), Watkin et al. (2015) identified a heterozygous c.721G-A transition (c.721G-A, NM_004371.3) in the COPA gene, resulting in a glu241-to-lys (E241K) substitution at a conserved residue in the WD40 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against 20 control exomes. It segregated with the disorder in the family, but there was evidence of incomplete penetrance. In vitro functional expression assays showed that the mutation caused impaired binding to a dilysine reporter, suggesting that it causes a defect in retrograde transport from the Golgi to the endoplasmic reticulum.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine, SCV000256757.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	yes	research	PubMed (1)
2	not provided	3	not provided	yes	research	PubMed (1)

Description

Segregates with the phenotype in an affected family, in vitro functional studies. The family showed incomplete penetrance, with unaffected carriers over six generations.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	discovery		5	not provided	1	not provided
2	inherited	no	not provided	not provided	discovery		3	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001395665.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect COPA protein function (PMID:¬†25894502). This variant has been observed to be de novo in an individual affected with autoimmune interstitial lung, joint, and kidney disease and segregates with disease in several families (PMID: 29137621, 25894502). ClinVar contains an entry for this variant (Variation ID: 199256) This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 241 of the COPA protein (p.Glu241Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807015.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderated, PM6 moderated, PP1 strong, PP2 supporting, PP3 supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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