ClinVar Miner

Submissions for variant NM_152594.3(SPRED1):c.1006G>A (p.Val336Ile) (rs373477920)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493530 SCV000582542 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing The V336I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge; however, it was observed to co-occur in a patient tested at GeneDx with another known pathogenic variant. The V336I variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V336I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species and Isoleucine is present many species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000819475 SCV000960139 uncertain significance Legius syndrome 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 336 of the SPRED1 protein (p.Val336Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs373477920, ExAC 0.003%). This variant has not been reported in the literature in individuals with SPRED1-related conditions. ClinVar contains an entry for this variant (Variation ID: 429870). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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