ClinVar Miner

Submissions for variant NM_001089.3(ABCA3):c.875A>T (p.Glu292Val) (rs149989682)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224775 SCV000281469 pathogenic not provided 2015-01-19 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000224775 SCV000345890 pathogenic not provided 2016-09-12 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000615487 SCV000711274 likely pathogenic Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies; Diffuse interstitial pulmonary fibrosis 2018-08-13 criteria provided, single submitter clinical testing The p.Glu292Val variant in ABCA3 has been reported in 22 compound heterozygous a nd 2 homozygous individuals with various respiratory diseases, including idiopat hic pulmonary fibrosis, desquamative interstitial pneumonitis, neonatal respirat ory failure, and childhood interstitial lung disease (Bullard 2005, Shanklin 200 8, Copertino 2012, Epaud 2014, Coghlan 2014, Wambach 2014). A mouse knock-in mod el homozygous for the p.Glu292Val variant displayed phenotypes consistent with i nterstitial lung disease (Tomer 2013). This variant has been identified in 0.43% (543/126312) of European chromosomes, including 3 homozygotes, by the Genome Ag gregation Database (gnomAD,; dbSNP rs149989682 ) and is reported in ClinVar (Variation ID: 203381). Please note that for diseas es with recessive inheritance, pathogenic variants may be present at a low frequ ency in the general population. Computational prediction tools and conservation analysis suggest that the p.Glu292Val variant may impact the protein, though thi s information is not predictive enough to determine pathogenicity. In summary, a lthough additional studies are required to fully establish its clinical signific ance, the p.Glu292Val variant is likely pathogenic. ACMG/AMP Criteria applied: P M3_Very Strong; PS3; PP3; BS1_Supporting.
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735281 SCV000854434 likely pathogenic Pulmonary arterial hypertension; Respiratory insufficiency; Pulmonary insufficiency criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000185556 SCV000886879 pathogenic Surfactant metabolism dysfunction, pulmonary, 3 2019-02-04 criteria provided, single submitter clinical testing This ABCA3 variant (rs149989682) is present in large population datasets (gnomAD: 660/282370 total alleles; 0.23%; 3 homozygotes). Five submitters in ClinVar classify this variant as either pathogenic or likely pathogenic. This variant has been reported in numerous affected individuals, both in the compound heterozygous and homozygous state. Multiple functional studies have demonstrated that this variant disrupts ATP hydrolysis and decreases phospholipid transport across the lamellar body membrane. This variant is considered pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000185556 SCV000914713 pathogenic Surfactant metabolism dysfunction, pulmonary, 3 2017-04-27 criteria provided, single submitter clinical testing Across a selection of the available literature the ABCA3 c.875T>A (p.Glu292Val) variant has been reported in a total of 36 patients with various pulmonary disorders, including in ten in a compound heterozygous state with a second missense or intronic variant, and in 26 in a heterozygous state in whom a second variant was not identified (Bullard et al. 2005; Garmany et al. 2008; Copertino et al. 2012; Baekvad-Hansen et al. 2012; Wambach et al. 2012). The variant was reported in three of 638 controls and at a frequency of 0.00454 in the European American population of the Exome Sequencing Project. Functional studies demonstrated that the p.Glu292Val variant exhibits correct cellular localization but moderately impaired transport function, and induces loss of epithelial cell differentiation in lung alveolar epithelia type II cells (Matsumura et al. 2008; Kaltenborn et al. 2011). Based on the collective evidence, the p.Glu292Val variant is classified as pathogenic for pulmonary surfactant metabolism dysfunction. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000224775 SCV001785976 uncertain significance not provided 2020-03-20 criteria provided, single submitter clinical testing Variant found to be over-represented in newborns with respiratory distress syndrome suggesting that E292V or its haplotype impart increased genetic risk for RDS (Garmany et al., 2008); Published functional studies demonstrate that the variant contributes to loss of epithelial cell differentiation (Kaltenborn et al., 2012); 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: 32238781, 31980526, 29566461, 18317237, 17597647, 15976379, 22304854, 29255193, 29569581, 18246475, 22145626, 22800827, 29505158, 27374344, 28034695, 25553246, 30609409, 29431110, 24871971, 23166334, 27516224, 22866751, 22434821, 18603241, 24136335, 18676873, 25073622)
Division of Human Genetics,Children's Hospital of Philadelphia RCV000185556 SCV000238440 likely pathogenic Surfactant metabolism dysfunction, pulmonary, 3 2015-01-08 no assertion criteria provided research The heterozygous variant in the ABCA3 gene (c.875A>T; p.Glu292Val) is considered likely pathogenic. According to Germany et al, the prevalence of this variant is 1:277 (PMID: 18317237) representing the most common ABCA3 variant associated with childhood interstitial lung disease. This variant has been published as a compound heterozygous variant in multiple affected individuals (PMID: 15976379, 22304854) and as a homozygous variant (PMID: 24871971). This variant represents a non-conservative amino acid change at highly conserved amino acid and nucleotide positions while not being located in a functional domain. In the ExAC database there are 271 alleles out of 121060 tested positive for this change.
Clinical Genomics Program, Stanford Medicine RCV000185556 SCV001371857 pathogenic Surfactant metabolism dysfunction, pulmonary, 3 2018-10-03 no assertion criteria provided clinical testing The p.Glu292Val variant in the ABCA3 gene has been previously reported with a second ABCA3 variant in >20 unrelated individuals with a range of pulmonary phenotypes, including respiratory distress, interstitial lung disease, and pulmonary fibrosis, which most commonly presented neonatally or in early childhood (Bullard et al. 2005; Doan et al. 2008; Copertino et al. 2012; Wambach et al. 2012; Turcu et al. 2013; Soares et al. 2013; Epaud et al. 2013; Coghlan et al. 2014; Wambach et al. 2014; Kröner et al. 2017; Akil et al. 2018). Compared to frameshift or nonsense pathogenic variants in the ABCA3 gene, the p.Glu292Val variant has been suggested to result in milder disease severity, with many individuals surviving into childhood or adulthood (Bullard et al. 2005; Copertino et al. 2012; Turcu et al. 2013; Epaud et al. 2013). Functional studies of the p.Glu292Val variant consistently demonstrate a deleterious effect and suggest a partial loss of ABCA3 protein activity (Wambach et al. 2016; Matsumura et al. 2018; Schindlbeck et al. 2018). In a large population database, the variant was identified in 543/126312 (0.43%) European chromosomes, including 3 homozygous individuals (Genome Aggregation Database, This frequency may suggest reduced penetrance of this allele. Additionally, individuals that are heterozygous for the p.Glu292Val variant are reported to have an increased risk for neonatal respiratory distress (Wambach et al. 2012 and Naderi et al. 2014). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Glu292Val variant as pathogenic for autosomal recessive surfactant metabolism dysfunction, pulmonary, 3. [ACMG evidence codes used: PS3, PS4].

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