ClinVar Miner

Submissions for variant NM_002317.7(LOX):c.1044T>A (p.Ser348Arg)

dbSNP: rs1561417568
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001592940 SCV001826781 likely pathogenic not provided 2023-08-07 criteria provided, single submitter clinical testing Published functional studies suggest a damaging effect as this variant leads to reduced enzymatic activity (Guo et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26838787, 29961567)
Invitae RCV001592940 SCV002166900 likely pathogenic not provided 2023-12-17 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 348 of the LOX protein (p.Ser348Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with thoracic aortic aneurysm and dissection (PMID: 26838787; Invitae). ClinVar contains an entry for this variant (Variation ID: 617849). 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 LOX protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LOX function (PMID: 26838787). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV002397522 SCV002704868 uncertain significance Cardiovascular phenotype 2024-02-16 criteria provided, single submitter clinical testing The p.S348R variant (also known as c.1044T>A), located in coding exon 5 of the LOX gene, results from a T to A substitution at nucleotide position 1044. The serine at codon 348 is replaced by arginine, an amino acid with dissimilar properties. This variant has been detected in individuals with aortic aneurysm and/or features of connective tissue disorders (Guo DC et al. Circ. Res., 2016 Mar;118:928-34; external communication). Functional studies from one group indicated this variant to result in reduced amount of active protein and reduce enzyme activity compared to wild type; however, additional evidence is needed to confirm this finding (Guo DC et al. Circ. Res., 2016 Mar;118:928-34). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Center for Mendelian Genomics, University of Washington RCV000755145 SCV000882967 pathogenic Congenital aneurysm of ascending aorta; Acute aortic dissection 2016-01-12 no assertion criteria provided research
GenomeConnect, ClinGen RCV003227848 SCV003925466 not provided Aortic aneurysm, familial thoracic 10 no assertion provided phenotyping only Variant interpreted as Likely pathogenic and reported on 06-24-2022 by GeneDx. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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