ClinVar Miner

Submissions for variant NM_022455.4(NSD1):c.7576C>T (p.Pro2526Ser) (rs373932824)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082142 SCV000114088 uncertain significance not provided 2015-07-02 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV001172456 SCV000194283 likely benign not specified 2017-09-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515435 SCV000611495 uncertain significance Beckwith-Wiedemann syndrome; Sotos syndrome 1 2017-05-23 criteria provided, single submitter clinical testing
Mendelics RCV000146950 SCV001137040 uncertain significance Sotos syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001245804 SCV001419115 uncertain significance Beckwith-Wiedemann syndrome 2019-03-22 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 2526 of the NSD1 protein (p.Pro2526Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs373932824, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in three members of a family affected with suspected Sotos syndrome. However, all affected members also carried another heterozygous variant of uncertain significance (p.Leu2081Val) in the NSD1 gene (PMID: 15452385). ClinVar contains an entry for this variant (Variation ID: 96077). 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 serine 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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