ClinVar Miner

Submissions for variant NM_152594.3(SPRED1):c.1282C>T (p.Arg428Cys) (rs941091989)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413238 SCV000490994 uncertain significance not specified 2015-11-13 criteria provided, single submitter clinical testing The R428C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R428C 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 in the SPR domain where amino acids with similar properties to Argininie are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. No missense variants have been reported in nearby residues in the Human Gene Mutation Database in association with any RASopathy disorder (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001368168 SCV001564551 uncertain significance Legius syndrome 2020-06-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 428 of the SPRED1 protein (p.Arg428Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SPRED1-related conditions. ClinVar contains an entry for this variant (Variation ID: 372629). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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