ClinVar Miner

Submissions for variant NM_022455.5(NSD1):c.7391G>A (p.Arg2464His)

gnomAD frequency: 0.00001  dbSNP: rs587784216
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000146947 SCV000194280 benign not specified 2013-02-08 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003231336 SCV002219504 uncertain significance Sotos syndrome 2021-09-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2464 of the NSD1 protein (p.Arg2464His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs587784216, ExAC 0.006%). This variant has not been reported in the literature in individuals with NSD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 159438). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NSD1 protein function. 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.
Neuberg Centre For Genomic Medicine, NCGM RCV003231336 SCV004176376 uncertain significance Sotos syndrome 2023-02-14 criteria provided, single submitter clinical testing The missense c.7391G>A(p.Arg2464His) variant in NSD1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency of 0.002% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database with varying interpretation: Benign / Uncertain Significance. The amino acid Arg at position 2464 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg2464His in NSD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Uncertain Significance.

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