Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000221771 | SCV000271306 | pathogenic | Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies | 2015-02-26 | criteria provided, single submitter | clinical testing | The p.Arg43His variant in ABCA3 has been previously reported in 1 homozygous inf ant with interstitial lung disease (ILD) and in 3 compound heterozygous infants/ children with ILD (Doan 2008, Agrawal 2012, Wambach 2014). In addition, two othe r variants at this codon (p.Arg43Leu and p.Arg43Cys) have each been reported in 2 compound heterozygous children with ILD and one of these variants (p.Arg43Cys) segregated with disease in an affected relative, suggesting that changes to thi s residue are not tolerated (Brasch 2006, Garmany 2006, Agrawal 2012, Wambach 20 14). The p.Arg43His variant has been identified in 1/66674 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Alth ough this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational predic tion tools and conservation analysis do not provide strong support for or agains t an impact the protein. In summary, this variant meets our criteria to be class ified as pathogenic for ILD in an autosomal recessive manner(http://www.partners .org/personalizedmedicine/LMM). |
| Johns Hopkins Genomics, |
RCV001804948 | SCV002051769 | pathogenic | Interstitial lung disease due to ABCA3 deficiency | 2021-12-06 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002381741 | SCV002694113 | pathogenic | Hereditary pulmonary alveolar proteinosis | 2022-10-08 | criteria provided, single submitter | clinical testing | The p.R43H pathogenic mutation (also known as c.128G>A), located in coding exon 2 of the ABCA3 gene, results from a G to A substitution at nucleotide position 128. The arginine at codon 43 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in the homozygous state or in conjunction with other ABCA3 disease-causing variants in multiple individuals with ABCA3-related surfactant dysfunction (Doan ML et al. Thorax, 2008 Apr;63:366-73; Agrawal A et al. Pediatr Res, 2012 Jun;71:633-7; Wambach JA et al. Am J Respir Crit Care Med, 2014 Jun;189:1538-43; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV003556277 | SCV004296371 | pathogenic | not provided | 2023-10-11 | 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 43 of the ABCA3 protein (p.Arg43His). This variant is present in population databases (rs754714105, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive childhood interstitial lung disease (PMID: 18024538, 24871971). ClinVar contains an entry for this variant (Variation ID: 228321). 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 ABCA3 protein function. This variant disrupts the p.Arg43 amino acid residue in ABCA3. Other variant(s) that disrupt this residue have been observed in individuals with ABCA3-related conditions (PMID: 22337229, 24871971), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |