Submissions for variant NM_001089.3(ABCA3):c.3241C>T (p.Arg1081Trp)

dbSNP: rs369277188

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001117044	SCV001275199	uncertain significance	Interstitial lung disease due to ABCA3 deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV003565455	SCV004313426	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1081 of the ABCA3 protein (p.Arg1081Trp). This variant is present in population databases (rs369277188, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive ABCA3-related conditions (PMID: 24871971, 32392962, 33359301). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 885444). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Clinical Genomics Program, Stanford Medicine	RCV001117044	SCV001427016	uncertain significance	Interstitial lung disease due to ABCA3 deficiency	2018-10-03	no assertion criteria provided	clinical testing	The p.Arg1081Trp variant in the ABCA3 gene has not been previously reported in association with disease. This variant was determined to be in trans with the pathogenic p.Glu292Val variant in this individual. However, it is unclear if this individual’s pulmonary findings are due to genetic causes or secondary to prematurity. The p.Arg1081Trp variant has been identified in 9/126552 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools predict that the p.Arg1081Trp variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Arg1081Trp variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2, PP3].