Submissions for variant NM_001089.3(ABCA3):c.3784A>G (p.Ser1262Gly)

gnomAD frequency: 0.00117  dbSNP: rs35089233

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000272311	SCV000395821	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.
GeneDx	RCV001556074	SCV001777588	uncertain significance	not provided	2021-02-24	criteria provided, single submitter	clinical testing	Identified in an individual with familial pulmonary fibrosis, however the variant did not segregate with the disease in the family (van Moorsel et al., 2010); Identified in control populations and individuals heterozygous for the variant did not differ in lung function from individuals with wildtype genotype (Baekvad-Hansen et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32196812, 22866751, 20849526, 20656946)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001556074	SCV002493369	benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002365372	SCV002625784	uncertain significance	Hereditary pulmonary alveolar proteinosis	2018-01-22	criteria provided, single submitter	clinical testing	The p.S1262G variant (also known as c.3784A>G), located in coding exon 22 of the ABCA3 gene, results from an A to G substitution at nucleotide position 3784. The serine at codon 1262 is replaced by glycine, an amino acid with similar properties. In one study, this variant was detected in conjunction with a pathogenic SFTPC mutation in two siblings with familial pulmonary fibrosis, who inherited p.S1262G from a healthy parent (Vvan Moorsel CH et al. Am. J. Respir. Crit. Care Med., 2010 Dec;182:1419-25). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003922339	SCV004740592	likely benign	ABCA3-related disorder	2022-02-01	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).