ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.575T>A (p.Leu192Gln) (rs879253996)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000237068 SCV000293106 uncertain significance not provided 2015-09-21 criteria provided, single submitter clinical testing The c.575 T>A variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Multiple in silico algorithms predict that c.575 T>A may create a new cryptic splice acceptor site in intron 5, leading to abnormal splicing; however, this change is downstream of the natural splice acceptor site. Additionally, in the absence of RNA/functional studies the actual effect of the variant is unknown. If c.575 T>A does not alter splicing it will result in the L192Q missense substitution. The L192Q variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. A different amino acid substitution at this same position (L192P) and other missense variants in nearby residues (Q196R, A199P, F202V) have been reported in the Human Gene Mutation Database in association with SMARD1 (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

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