Submissions for variant NM_001089.3(ABCA3):c.839G>A (p.Arg280His)

gnomAD frequency: 0.00141  dbSNP: rs143008553

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219325	SCV000271479	uncertain significance	not specified	2015-12-09	criteria provided, single submitter	clinical testing	The p.Arg280His variant in ABCA3 has been reported in 1 individual with adult id iopathic interstitial pneumonia (Van Moorsel, 2010). It has been identified in 0 .15% (100/66624) of European chromosomes by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs143008553). Computational prediction tools and conservation analysis suggest that this variant may impact the protei n, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg280His variant is uncertain.
Illumina Laboratory Services, Illumina	RCV000308878	SCV000396148	uncertain significance	Interstitial lung disease due to ABCA3 deficiency	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Johns Hopkins Genomics, Johns Hopkins University	RCV000308878	SCV001431524	uncertain significance	Interstitial lung disease due to ABCA3 deficiency	2020-08-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001477709	SCV001681956	likely benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000308878	SCV002556742	uncertain significance	Interstitial lung disease due to ABCA3 deficiency	2021-05-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433932	SCV002680231	uncertain significance	Hereditary pulmonary alveolar proteinosis	2019-02-20	criteria provided, single submitter	clinical testing	The p.R280H variant (also known as c.839G>A), located in coding exon 5 of the ABCA3 gene, results from a G to A substitution at nucleotide position 839. The arginine at codon 280 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in the heterozygous state, in an adult patient with sporadic pulmonary fibrosis and in a newborn infant with neonatal respiratory distress syndrome (RDS) (van Moorsel CH et al. Am. J. Respir. Crit. Care Med., 2010 Dec;182:1419-25; Wambach JA et al. Pediatrics, 2012 Dec;130:e1575-82); a second alteration was not identified in either patient. In a newborn with diffuse parenchymal lung disease (DPLD) p.R280H was detected in the heterozygous state with a second alteration; phase was not confirmed, and the clinical significance and possible contribution of this variant to the patient's phenotype is unclear (Kröner C et al. Thorax, 2016 Aug; [Epub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV003448905	SCV004175720	uncertain significance	Bullous lung disease	2023-09-19	criteria provided, single submitter	clinical testing	Heterozygous variant NM_001089:c.839G>A (p.Arg280His) in the ABCA3 gene was found on WES data in male proband (20 y.o., Caucasian) with bullous lung disease and spontaneous pneumothorax. No additional rare candidate variants (Class III-V of pathogenicity) were found in this proband. This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.0008265 (Date of access 13-09-2023). Clinvar contains an entry for this variant (Variation ID: 228421). This variant has been reported in 4 studies in patients with primary lung diseases with variable phenotypes, and in most cases in compound heterozygous with other pathogenic alleles (PMID: 20656946‚ 23166334‚ 27516224, 33708521). Most in silico predictors are inconclusive in the results (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Variant of Uncertain Significance (VUS) with following criteria selected: PM2.
GeneDx	RCV001477709	SCV005325825	likely pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27516224, 23166334, 20656946, 36863776, 36808083, 36404394, 25712598, 24871971, 24115460, 37780198, 33708521)
PreventionGenetics, part of Exact Sciences	RCV004739605	SCV005350619	uncertain significance	ABCA3-related disorder	2024-08-26	no assertion criteria provided	clinical testing	The ABCA3 c.839G>A variant is predicted to result in the amino acid substitution p.Arg280His. This variant has been reported in an infant with neonatal respiratory distress without a second variant specified (Supp. Table 13, Wambach et al. 2012. PubMed ID: 23166334). It has also been reported in an individual with diffuse parenchymal lung disease with a second ABCA3 variant, though the phase of the variants was not specified (Kröner et al. 2017. PubMed ID: 27516224), and in a full term infant with severe respiratory distress syndrome in the compound heterozygous state with ABCA3 c.1897-1G>C (Wang et al. 2021. PubMed ID: 33708521). This variant is reported in 0.19% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.