ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Invitae RCV000229299 SCV000291522 uncertain significance Legius syndrome 2020-10-25 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.
GeneDx RCV001705204 SCV000730682 likely benign not provided 2019-02-15 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21548021, 19920235, 22753041, 32107864)
Illumina Clinical Services Laboratory,Illumina RCV000229299 SCV001280217 uncertain significance Legius syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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