ClinVar Miner

Submissions for variant NM_152594.3(SPRED1):c.587C>T (p.Thr196Ile) (rs147474792)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000214558 SCV000730682 likely benign not specified 2017-05-03 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000229299 SCV000291522 uncertain significance Legius syndrome 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 196 of the SPRED1 protein (p.Thr196Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs147474792, ExAC 0.03%). This variant has been reported in an individual with neurofibromatosis type 1-like syndrome (PMID: 19920235) and in a individual with café-au-lait macules and no other NF1-related signs (PMID: 21548021).  ClinVar contains an entry for this variant (Variation ID: 229269). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In addition, an experimental study reported that this missense change does not adversely affect protein function (PMID: 19920235), but the evidence in this report is insufficient to demonstrate that conclusively. In summary, this is a novel missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000214558 SCV000272454 uncertain significance not specified 2015-10-08 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Thr196Ile var iant in SPRED1 has been reported in 2 individuals with multiple cafe-au-lait mac ules (CALMs), with or without freckling, who were negative for deleterious NF1 v ariants (Messiaen 2009, Spencer 2011). This variant has also been identified in 11/65518 European chromosomes by the Exome Aggregation Consortium (ExAC, http://; dbSNP rs147474792). In vitro functional studies suggest that the p.Thr196Ile variant may not impact protein function; however, these ty pes of assays may not accurately represent biological function (Messiaen 2009). Additional computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predict ive enough to rule out pathogenicity. In summary, while the clinical significanc e of the p.Thr196Ile variant is uncertain, these data suggest that it is more li kely to be benign.

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