ClinVar Miner

Submissions for variant NM_001089.3(ABCA3):c.2296C>T (p.Pro766Ser) (rs45592239)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000155453 SCV000701592 likely benign not specified 2016-10-14 criteria provided, single submitter clinical testing
Invitae RCV000888350 SCV001031980 likely benign not provided 2019-12-31 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV001007589 SCV001167236 uncertain significance Surfactant metabolism dysfunction, pulmonary, 3 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 Clinical Services Laboratory,Illumina RCV001007589 SCV001274389 uncertain significance Surfactant metabolism dysfunction, pulmonary, 3 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 2021-06-29 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: 27535533, 23625987, 16641205, 22866751, 24871971)

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