ClinVar Miner

Submissions for variant NM_152594.3(SPRED1):c.1202G>T (p.Cys401Phe) (rs779058019)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000559526 SCV000645815 uncertain significance Legius syndrome 2020-09-06 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 401 of the SPRED1 protein (p.Cys401Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs779058019, ExAC 0.003%). This variant has not been reported in the literature in individuals with a SPRED1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). In summary, this variant has uncertain impact on SPRED1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001584299 SCV001821424 uncertain significance not specified 2021-08-29 criteria provided, single submitter clinical testing Variant summary: SPRED1 c.1202G>T (p.Cys401Phe) results in a non-conservative amino acid change located in the Sprouty domain (IPR007875) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251246 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1202G>T has been reported in the literature as a VUS in the settings of multigene panel testing in one individual within a cohort of Finnish individuals affected with dilated cardiomyopathy (DCM) (example, Akinrinade_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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