Submissions for variant NM_001089.3(ABCA3):c.4012G>A (p.Ala1338Thr)

gnomAD frequency: 0.00038  dbSNP: rs149871856

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000315299	SCV000395816	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.
Ambry Genetics	RCV002356427	SCV002622200	uncertain significance	Hereditary pulmonary alveolar proteinosis	2017-07-01	criteria provided, single submitter	clinical testing	The p.A1338T variant (also known as c.4012G>A), located in coding exon 23 of the ABCA3 gene, results from a G to A substitution at nucleotide position 4012. The alanine at codon 1338 is replaced by threonine, an amino acid with similar properties. 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.
Fulgent Genetics, Fulgent Genetics	RCV000315299	SCV002814877	uncertain significance	Interstitial lung disease due to ABCA3 deficiency	2022-05-26	criteria provided, single submitter	clinical testing
Invitae	RCV002520994	SCV003298249	benign	not provided	2024-01-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155158	SCV003844866	uncertain significance	not specified	2023-02-16	criteria provided, single submitter	clinical testing	Variant summary: ABCA3 c.4012G>A (p.Ala1338Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 249974 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCA3 causing Pulmonary surfactant metabolism dysfunction (0.00044 vs 0.0011), allowing no conclusion about variant significance. c.4012G>A has been reported in the literature in a compound heterozygous individual affected with neonatal respiratory disease without evidence of cosegregation (Kroner_2017). This report does not provide unequivocal conclusions about association of the variant with Pulmonary surfactant metabolism dysfunction. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=3) or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003950084	SCV004767304	likely benign	ABCA3-related condition	2020-02-21	criteria provided, single submitter	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).