Submissions for variant NM_001089.3(ABCA3):c.2296C>T (p.Pro766Ser)

gnomAD frequency: 0.00170  dbSNP: rs45592239

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155453	SCV000205144	uncertain significance	not specified	2014-11-05	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Pro766Ser var iant in ABCA3 has been reported in at least 10 individuals with various pulmonar y phenotypes (Baekvad-Hansen 2012). In addition, this variant has been identifie d in 0.26% (22/8600) of European American chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs45592239). Computational prediction tools and conservation analysis suggest that the p.Pro766Ser variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In fact, 2 fish species (southern platyfish and spotted gar) carry a serine (Ser) at this position, suggesting that this change may be tolerated. In summary, while the clinical significance of the p.Pro766Ser varian t is uncertain, its frequency and the presence of the variant amino acid in othe r species suggests that it is more likely to be benign.
Eurofins Ntd Llc (ga)	RCV000155453	SCV000701592	likely benign	not specified	2016-10-14	criteria provided, single submitter	clinical testing
Invitae	RCV000888350	SCV001031980	likely benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV001007589	SCV001167236	uncertain significance	Interstitial lung disease due to ABCA3 deficiency	2019-10-28	criteria provided, single submitter	clinical testing	This ABCA3 variant has been reported in the heterozygous state and as part of a complex allele with p.Leu960Phe. This patient does not carry the latter variant and the clinical significance of p.Pro766Ser alone is unclear. There are conflicting interpretations of the pathogenicity of this variant in ClinVar. One submitter classified it as a variant of uncertain clinical significance and one as likely benign. Of three bioinformatics tools queried, two predict that the substitution would be damaging, while one predicts that it would be tolerated. The proline residue at this position is highly evolutionarily conserved across most higher order species. Due to insufficient evidence, we consider the clinical significance of c.2296C>T to be uncertain at this time.
Illumina Laboratory Services, Illumina	RCV001007589	SCV001274389	uncertain significance	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000888350	SCV001779723	uncertain significance	not provided	2022-05-18	criteria provided, single submitter	clinical testing	Observed in the homozygous state in three unrelated patients with interstitial lung disease and in the compound heterozygous state with a frameshift variant in another patient with interstitial lung disease (Wambach et al., 2014); in all cases P766S was observed in cis with L960F; Observed in the heterozygous state in four individuals with variable pulmnoary phenotypes including asthma, COPD, and interstitial lung disease and in 121 patients from a general population health study (Copenhagen City Heart study) without a significant pulmonary phenotype, including one individual who was compound heterozygous for P766S and another missense variant (Baekvad-Hansen et al., 2012); Identified in the compound heterozygous state along with a frameshift variant in an infant with interstitial lung disease (Garmany et al., 2006); P766S was in cis with L960F in this individual; Identified in the heterozygous state along with L960F and another missense variant in a patient with interstitial lung disease (Turcu et al., 2013); the phase of these variants was not determined; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24871971, 22866751, 16641205, 23625987, 27535533, 34638622, 35170262)
Ambry Genetics	RCV002444640	SCV002734812	uncertain significance	Hereditary pulmonary alveolar proteinosis	2021-01-25	criteria provided, single submitter	clinical testing	The p.P766S variant (also known as c.2296C>T), located in coding exon 15 of the ABCA3 gene, results from a C to T substitution at nucleotide position 2296. The proline at codon 766 is replaced by serine, an amino acid with similar properties. This variant was identified in cis with p.L960F and in trans with a frameshift alteration in an infant with progressive lung disease and a histopathologic diagnosis of pulmonary alveolar proteinosis (Garmany TH et al. Pediatr. Res., 2006 Jun;59:801-5). In another study, the complex allele, p.[P766S; L960F], was identified in four individuals with severe pulmonary symptoms and a third ABCA3 alteration in trans (Wambach JA et al. Am. J. Respir. Crit. Care Med., 2014 Jun;189:1538-43). The p.P766S variant was identified in conjunction with two additional ABCA3 alterations in an individual with interstitial lung disease and chronic interstitial pneumonitis diagnosed at one year of age and a history of respiratory distress syndrome at birth; however, the phase of the alterations was not provided (Turcu S et al. Arch. Dis. Child., 2013 Jul;98:490-5).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. Based on available evidence to date, the clinical significance of this variant remains unclear.