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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000345429	SCV001373860	pathogenic	not provided	2024-02-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1952 of the NSD1 protein (p.Arg1952Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Sotos syndrome (PMID: 15942875, 17565729, 22924495, 34033256). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 279858). 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 expected to disrupt NSD1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects NSD1 function (PMID: 21196496, 24412544). For these reasons, this variant has been classified as 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	no assertion criteria provided	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.