Submissions for variant NM_001089.3(ABCA3):c.1183C>T (p.Arg395Trp)

gnomAD frequency: 0.00004  dbSNP: rs201681616

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000269298	SCV000396070	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.
Ambry Genetics	RCV002338905	SCV002638333	uncertain significance	Hereditary pulmonary alveolar proteinosis	2017-07-01	criteria provided, single submitter	clinical testing	The p.R395W variant (also known as c.1183C>T), located in coding exon 8 of the ABCA3 gene, results from a C to T substitution at nucleotide position 1183. The arginine at codon 395 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005055875	SCV005715612	uncertain significance	not provided	2024-12-11	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 395 of the ABCA3 protein (p.Arg395Trp). This variant is present in population databases (rs201681616, gnomAD 0.02%). This missense change has been observed in individual(s) with unexplained respiratory distress syndrome (PMID: 33708521). ClinVar contains an entry for this variant (Variation ID: 318558). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ABCA3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.