ClinVar Miner

Submissions for variant NM_022455.4(NSD1):c.6014G>A (p.Arg2005Gln) (rs587784174)

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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 RCV000146903 SCV000194232 pathogenic Sotos syndrome 1 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000286929 SCV000329441 pathogenic not provided 2017-04-06 criteria provided, single submitter clinical testing The R2005Q variant in the NSD1 gene has been reported previously in at least two individuals with Sotos syndrome, and was found to be de novo in one of these individuals (Douglas et al., 2003; Waggoner et al., 2005). NSD1 is a SET domain histone methyltransferase (HKMT) that primarily dimethylates nucleosomal histone H3 lysine 36 (H3K36), and a functional study found R2005Q reduced the activity of the H3K36 HKMT (Qiao et al., 2011). The R2005Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R2005Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Based on currently available evidence, we interpret R2005Q as a pathogenic variant, and its presence is consistent with a diagnosis of Sotos syndrome.
Invitae RCV000793328 SCV000932676 likely pathogenic Beckwith-Wiedemann syndrome 2018-07-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 2005 of the NSD1 protein (p.Arg2005Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Sotos syndrome (PMID: 12464997), and in another individual referred for genetic testing of Sotos syndrome (PMID: 16247291). ClinVar contains an entry for this variant (Variation ID: 159395). Experimental studies have shown that this missense change has greatly reduced H3K36 histone methyltransferase activities in vitro (PMID: 21196496). The observation of one or more missense substitutions at this codon (p.Arg2005Gly) in affected individuals suggests that this may be a clinically significant residue (PMID: 26690673). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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