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

gnomAD frequency: 0.00001  dbSNP: rs794727993

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000180776	SCV000256756	pathogenic	Autoimmune interstitial lung disease-arthritis syndrome	2015-04-20	criteria provided, single submitter	research	Segregates with the phenotype in two affected families. One family showed incomplete penetrance, with one unaffected carrier over four generations.
Invitae	RCV000180776	SCV000774975	pathogenic	Autoimmune interstitial lung disease-arthritis syndrome	2023-12-10	criteria provided, single submitter	clinical testing	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.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000180776	SCV000930528	pathogenic	Autoimmune interstitial lung disease-arthritis syndrome	2019-08-01	criteria provided, single submitter	clinical testing	identified in different affected members of same family
Baylor Genetics	RCV000180776	SCV001530127	pathogenic	Autoimmune interstitial lung disease-arthritis syndrome	2018-05-07	criteria provided, single submitter	clinical testing	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]
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV003156081	SCV003845270	pathogenic	See cases	2022-12-21	criteria provided, single submitter	clinical testing
OMIM	RCV000180776	SCV000233264	pathogenic	Autoimmune interstitial lung disease-arthritis syndrome	2015-06-01	no assertion criteria provided	literature only