Submissions for variant NM_022455.5(NSD1):c.6014G>A (p.Arg2005Gln)

dbSNP: rs587784174

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV003231294	SCV000194232	pathogenic	Sotos syndrome	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000286929	SCV000329441	pathogenic	not provided	2023-10-04	criteria provided, single submitter	clinical testing	Segregates with disease in affected individuals from a single family referred for genetic testing at GeneDx; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect through reduction of H3K36 histone lysine methyltransferase activity (Qiao et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12464997, 33942996, 21196496, 27834868, 16247291, 16010675)
Labcorp Genetics (formerly Invitae), Labcorp	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.
Genome-Nilou Lab	RCV003231294	SCV002054962	likely pathogenic	Sotos syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003231294	SCV005044740	pathogenic	Sotos syndrome		criteria provided, single submitter	clinical testing	The missense c.6014G>A p.Arg2005Gln variant in NSD1 gene has been reported in heterozygous state in individuals affected with Sotos syndrome Douglas J et al. 2003. Functional study found R2005Q reduced the activity of the H3K36 HKMT Qiao et al., 2011. The p.Arg2005Gln variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic/ Pathogenic. The amino acid change p.Arg2005Gln in NSD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 2005 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.