Submissions for variant NM_001089.3(ABCA3):c.2341G>A (p.Val781Met)

dbSNP: rs771821923

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000758249	SCV000395992	uncertain significance	Interstitial lung disease due to ABCA3 deficiency	2018-01-13	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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000758249	SCV000886889	uncertain significance	Interstitial lung disease due to ABCA3 deficiency	2019-02-22	criteria provided, single submitter	clinical testing	This ABCA3 variant (rs771821923) is rare in large population datasets (gnomAD: 5/251164 total alleles; 0.002%; no homozygotes). This variant has not been reported in the literature, to our knowledge. A single submitter in ClinVar classifies this as a variant of uncertain clinical significance (Variation ID: 318487). Of two bioinformatics tools queried, one predicts that the substitution would be possibly damaging, while the second predicts that it would be damaging. The valine residue at this position is not highly evolutionarily conserved across the species assessed. Bioinformatic analysis predicts that this variant would not affect normal exon 18 splicing, although this has not been confirmed experimentally to our knowledge. The clinical significance of c.2341G>A is uncertain at this time.
Ambry Genetics	RCV004021650	SCV004094273	uncertain significance	Hereditary pulmonary alveolar proteinosis	2023-08-22	criteria provided, single submitter	clinical testing	The c.2341G>A (p.V781M) alteration is located in exon 18 (coding exon 15) of the ABCA3 gene. This alteration results from a G to A substitution at nucleotide position 2341, causing the valine (V) at amino acid position 781 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.