Submissions for variant NM_022455.5(NSD1):c.5854C>T (p.Arg1952Trp)

dbSNP: rs886041219

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000345429	SCV000329439	pathogenic	not provided	2016-03-15	criteria provided, single submitter	clinical testing	The R1952W pathogenic variant in the NSD1 gene has been reported previously in association with Sotos syndrome(Tatton-Brown et al., 2005; Saugier-Veber et al., 2007). Functional studies indicate that R1952W impairs the histonelysine methyltransferase activity of the NSD1 enzyme (Qiao et al., 2011). R1952W was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. This substitution occurs at a highlyconserved position that is predicted to be within the SET domain of the NSD1 protein. In silico analysis predicts thisvariant is probably damaging to the protein structure/function.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV003231427	SCV000782187	pathogenic	Sotos syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV003231427	SCV001373860	likely pathogenic	Sotos syndrome	2021-08-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 1952 of the NSD1 protein (p.Arg1952Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of Sotos syndrome (PMID: 15942875, 17565729, 22924495). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 279858). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects NSD1 function (PMID: 21196496; .24412544). 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.
Genome-Nilou Lab	RCV003231427	SCV002054956	likely pathogenic	Sotos syndrome	2021-07-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003909902	SCV004720854	likely pathogenic	NSD1-related disorder	2023-11-21	criteria provided, single submitter	clinical testing	The NSD1 c.5854C>T variant is predicted to result in the amino acid substitution p.Arg1952Trp. This variant has been reported in several individuals with suspected Sotos syndrome; in at least one individual, this variant was found to be de novo (Tatton-Brown et al. 2005. PubMed ID: 15942875; Fortin et al. 2021. PubMed ID: 34033256; Pohjola et al. 2012. PubMed ID: 22924495). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.