Submissions for variant NM_001089.3(ABCA3):c.367G>A (p.Asp123Asn)

gnomAD frequency: 0.00029  dbSNP: rs145087575

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150116	SCV000196940	likely benign	not specified	2014-08-14	criteria provided, single submitter	clinical testing	Asp123Asn in exon 6 of ABCA3: This variant is not expected to have clinical sign ificance due to a lack of conservation across species, including mammals. Of not e, 5 mammals (naked mole rat, weddell seal, elephant, opossum, and Tasmanian dev il) have an asparagine (Asn) at this position despite high nearby amino acid con servation. In addition, computational prediction tools do not suggest a high lik elihood of impact to the protein. This variant has also been identified in 6/860 0 of European American chromosomes by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS/; dbSNP rs145087575).
Mendelics	RCV000989468	SCV001139801	benign	Interstitial lung disease due to ABCA3 deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000989468	SCV001280597	uncertain significance	Interstitial lung disease due to ABCA3 deficiency	2017-08-29	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.
Ambry Genetics	RCV002453478	SCV002615262	uncertain significance	Hereditary pulmonary alveolar proteinosis	2014-06-06	criteria provided, single submitter	clinical testing	The p.D123N variant (also known as c.367G>A), located in coding exon 3 of the ABCA3 gene, results from a G to A substitution at nucleotide position 367. The aspartic acid at codon 123 is replaced by asparagine, an amino acid with highly similar properties. This variant was observed with a pathogenic alteration in the SFTPC gene in a patient affected with interstitial lung disease (ILD) and his daughter with pathology findings of ILD. A second daughter with the SFTPC mutation only was not found to have any indication of ILD (Crossno PF et al. Chest. 2010;137(4):969-73). This variant was previously reported in the SNPDatabase as rs145087575. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.05% (6/12996) total alleles studied and 0.07% (6/8600) European American alleles. This amino acid position is not well conserved on sequence alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Since clinical data on this variant is limited at this time, its clinical significance is unclear.
Revvity Omics, Revvity	RCV000989468	SCV003824316	uncertain significance	Interstitial lung disease due to ABCA3 deficiency	2022-05-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV005089725	SCV005728167	uncertain significance	not provided	2024-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 123 of the ABCA3 protein (p.Asp123Asn). This variant is present in population databases (rs145087575, gnomAD 0.06%). 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: 162676). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.