Submissions for variant NM_001089.3(ABCA3):c.446C>T (p.Ala149Val)

gnomAD frequency: 0.00008  dbSNP: rs145483014

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Johns Hopkins Genomics, Johns Hopkins University	RCV001007602	SCV001167285	likely benign	Interstitial lung disease due to ABCA3 deficiency	2019-09-20	criteria provided, single submitter	clinical testing
Invitae	RCV001862749	SCV002223947	uncertain significance	not provided	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with valine at codon 149 of the ABCA3 protein (p.Ala149Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs145483014, ExAC 0.1%). This variant has not been reported in the literature in individuals affected with ABCA3-related conditions. ClinVar contains an entry for this variant (Variation ID: 816671). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Ambry Genetics	RCV002327228	SCV002636070	uncertain significance	Hereditary pulmonary alveolar proteinosis	2021-04-14	criteria provided, single submitter	clinical testing	The p.A149V variant (also known as c.446C>T), located in coding exon 3 of the ABCA3 gene, results from a C to T substitution at nucleotide position 446. The alanine at codon 149 is replaced by valine, an amino acid with similar properties. This variant was identified in one individual with severe respiratory disease with diffuse patchy ground-glass opacification and interlobular septal thickening on the chest CT; a second ABCA3 variant was not identified (Alsamri MT et al. Sci Rep, 2021 Feb;11:2715). It was also identified in one individual with asthma; however, the variant was not evaluated further in the study (Bækvad-Hansen M et al. Respir. Res., 2012 Aug;13:67). 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.
CeGaT Center for Human Genetics Tuebingen	RCV001862749	SCV004142953	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	ABCA3: BP4