Submissions for variant NM_001089.3(ABCA3):c.440C>T (p.Pro147Leu)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002333802	SCV002631876	likely pathogenic	Hereditary pulmonary alveolar proteinosis	2015-07-15	criteria provided, single submitter	clinical testing	The p.P147L variant (also known as c.440C>T), located in coding exon 3 of the ABCA3 gene, results from a C to T substitution at nucleotide position 440. The proline at codon 147 is replaced by leucine, an amino acid with some similar properties. This alteration was first reported in an infant with unexplained respiratory distress, desquamative interstitial pnemonia, who died under one year of age; this patient was confirmed to have another ABCA3 alteration (p.R155Q) in trans (Somaschini M et al. J Pediatr. 2007;150(6):649-53, 653.e1). This alteration was also reported in the homozygous state (due to paternal uniparental disomy) in an infant with respiratory failure, poor weight gain at birth, and interstitial infiltrates on CT; this patient underwent a lung transplantation at 3 months of age ( Hamvas A et al. J Pediatr. 2009;155(6):854-859.e1). This variant was previously reported in the SNPDatabase as rs200171469. Based on data from the 1000 Genomes Project, the T allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.83% (1/120) Colombian alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003560962	SCV004296369	pathogenic	not provided	2023-03-15	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 147 of the ABCA3 protein (p.Pro147Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features consistent with surfactant metabolism dysfunction (PMID: 17517255, 19647838, 24871971, 33110422). ClinVar contains an entry for this variant (Variation ID: 1740383). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA3 protein function. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526925	SCV005040301	likely pathogenic	Interstitial lung disease due to ABCA3 deficiency	2024-03-14	criteria provided, single submitter	clinical testing	Variant summary: ABCA3 c.440C>T (p.Pro147Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 227782 control chromosomes (gnomAD). c.440C>T has been reported in the literature in individuals affected with Pulmonary surfactant metabolism dysfunction (Somaschini_2007, Hamvas_2009, Wambach_2014, Jouza_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17517255, 19647838, 24871971, 33110422). ClinVar contains an entry for this variant (Variation ID: 1740383). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004545297	SCV005040783	likely pathogenic	Loeys-Dietz syndrome	2024-03-14	criteria provided, single submitter	clinical testing	Variant summary: SMAD3 c.440C>T (p.Pro147Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.8e-05 in 394710 control chromosomes (gnomAD v2.1 & v3). The observed variant frequency is approximately 30-fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD3 causing Loeys-Dietz Syndrome phenotype (1.3e-06), suggesting that the variant might be benign. To our knowledge, no occurrence of c.440C>T in individuals affected with Loeys-Dietz Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Fulgent Genetics, Fulgent Genetics	RCV004526925	SCV005646517	likely pathogenic	Interstitial lung disease due to ABCA3 deficiency	2024-03-13	criteria provided, single submitter	clinical testing