ClinVar Miner

Submissions for variant NM_001089.3(ABCA3):c.838C>T (p.Arg280Cys) (rs201299260)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000365922 SCV000396149 uncertain significance Surfactant metabolism dysfunction, pulmonary, 3 2017-04-27 criteria provided, single submitter clinical testing The ABCA3 c.838C>T (p.Arg280Cys) missense variant has been reported three studies in which it is found in three patients in a compound heterozygous state including in one child with interstitial lung disease secondary to ABCA3 deficiency in a compound heterozygous state with a second missense variant, in one infant with unexplained respiratory distress, in whom a second variant could not be identified and in a third patient with pulmonary surfactant deficiency, in cis with a stop-gained variant and in trans with a synonymous variant (Somaschini et al. 2007; Williamson et al. 2014; Jackson et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. Weichert et al. (2011) demonstrated that human alveolar epithelial A549 cells expressing the p.Arg280Cys variant partially impaired transport of the ABCA3 protein through the endoplasmic reticulum (ER) leading to retention in the ER compared to wild type. Based on the evidence, the p.Arg280Cys variant is classified likely pathogenic for pulmonary surfactant metabolism dysfunction. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825854 SCV000967338 uncertain significance not specified 2018-07-05 criteria provided, single submitter clinical testing The p.Arg280Cys variant in ABCA3 has been reported in the compound heterozygous state in 1 individual with interstitial lung disease (ILD) and has also been rep orted in cis with the p.Q1589X variant in ABCA3 in 2 individuals with ILD who c arried another variant in trans (Williamson 2014, Wambach 2014, Jackson 2015). I n vitro functional studies provide some evidence that the p.Arg280Cys variant ma y impact protein function (Weichert 2011). However, these types of assays may no t accurately represent biological function. This variant has been reported in Cl inVar (Variation ID: 318566) and has been identified in 30/111616 European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org/; dbSNP rs201299260). Computational prediction tools and conservation analys is suggest that the p.Arg280Cys variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. In summary, the cli nical significance of the p.Arg280Cys variant is uncertain. ACMG/AMP Criteria ap plied: PP3, PS3_Supporting, PM3_Supporting, BP2.
Johns Hopkins Genomics, Johns Hopkins University RCV000365922 SCV001167276 pathogenic Surfactant metabolism dysfunction, pulmonary, 3 2019-09-06 criteria provided, single submitter clinical testing This ABCA3 variant (rs201299260) is rare (<0.1%) in a large population dataset (gnomAD: 45/281924 total alleles; 0.016%; no homozygotes). Two submitters in ClinVar classify c.838C>T as a variant of uncertain clinical significance. This variant has been reported in numerous patients with respiratory distress. A functional study has demonstrated that this variant affects normal ABCA3 protein trafficking and folding. This variant is considered pathogenic.

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