Submissions for variant NM_001089.3(ABCA3):c.4085C>T (p.Ala1362Val)

gnomAD frequency: 0.00026  dbSNP: rs145251229

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Johns Hopkins Genomics, Johns Hopkins University	RCV000856676	SCV000999222	uncertain significance	Interstitial lung disease due to ABCA3 deficiency	2019-05-20	criteria provided, single submitter	clinical testing	This previously reported ABCA3 variant (rs145251229) has been identified in large population datasets and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within a subpopulation (gnomAD total: 72/282632 alleles; 0.02547%, no homozygotes). Two bioinformatic tools queried predict that this substitution would be tolerated, and the alanine residue at this position is not evolutionarily conserved across species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 27 splicing, although this has not been confirmed experimentally to our knowledge. Due to insufficient evidence that this variant is deleterious, the clinical significance of c.4085C>T is uncertain at this time.
Invitae	RCV000902436	SCV001046858	likely benign	not provided	2024-01-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000856676	SCV001278810	benign	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Ambry Genetics	RCV002319951	SCV002628948	uncertain significance	Hereditary pulmonary alveolar proteinosis	2023-06-26	criteria provided, single submitter	clinical testing	The p.A1362V variant (also known as c.4085C>T), located in coding exon 24 of the ABCA3 gene, results from a C to T substitution at nucleotide position 4085. The alanine at codon 1362 is replaced by valine, an amino acid with similar properties. This variant was reported in an 8-month-old infant born prematurely with chronic lung disease and pulmonary hypertension, requiring assisted ventilation; this variant was confirmed in trans with another ABCA3 alteration (Akimoto T et al. Pediatr. Res., 2014 Nov;76:453-8). This variant was previously reported in the SNPDatabase as rs145251229. Based on data from the 1000 Genomes Project, the T allele has an overall frequency of approximately 0.14% (3/2098) total alleles studied. The highest observed frequency was 1.69% (3/178) Japanese alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.02% (2/12996) total alleles studied and 0.02% (2/8600) European American alleles. This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this variant remains unclear.