ClinVar Miner

Submissions for variant NM_152594.3(SPRED1):c.1225_1226delinsTT (p.Ala409Phe) (rs1566877075)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000681186 SCV000808644 likely benign not provided 2018-04-12 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 RCV000818826 SCV000959460 uncertain significance Legius syndrome 2020-06-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with phenylalanine at codon 409 of the SPRED1 protein (p.Ala409Phe). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and phenylalanine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 561784). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001269110 SCV001448352 likely benign not specified 2020-11-23 criteria provided, single submitter clinical testing Variant summary: SPRED1 c.1225_1226delinsTT (p.Ala409Phe) results in a non-conservative amino acid change in 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 0.0002 in 282586 control chromosomes, predominantly at a frequency of 0.0018 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 320-fold of the estimated maximal expected allele frequency for a pathogenic variant in SPRED1 causing Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome) phenotype (5.6e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.1225_1226delinsTT in individuals affected with Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign/likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV001261039 SCV001438440 uncertain significance Noonan syndrome no assertion criteria provided clinical testing

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