Submissions for variant NM_022455.5(NSD1):c.6050G>A (p.Arg2017Gln)

dbSNP: rs587784177

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV003231297	SCV000194235	pathogenic	Sotos syndrome	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000290468	SCV000329438	pathogenic	not provided	2020-12-11	criteria provided, single submitter	clinical testing	Identified in multiple patients with Sotos Syndrome (Douglas et al., 2003; Tatton-Brown et al., 2005; Saugier-Veber et al., 2007; Kotilainen et al., 2009; Ha et al., 2016); Published functional studies demonstrate a damaging effect on the histone methyltransferase (HMT) activity (Qiao et al., 2011); Not observed in large population cohorts (Lek et al., 2016); 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: 16010675, 17565729, 12464997, 21196496, 15942875, 19876911, 27834868, 30719864)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415049	SCV000493005	likely pathogenic	Hypertelorism; Global developmental delay; Scoliosis; Hypoplasia of the corpus callosum; Delayed speech and language development; Delayed gross motor development; High anterior hairline	2014-05-14	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414978	SCV000493045	likely pathogenic	Preeclampsia; Tall stature; Overgrowth; Pointed chin; Delayed speech and language development; Macrocephaly; High forehead; Osteopenia; Increased body weight	2013-12-13	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV003231297	SCV000782188	pathogenic	Sotos syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV003231297	SCV000999348	pathogenic	Sotos syndrome		criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV003231297	SCV001367283	likely pathogenic	Sotos syndrome	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic.
Genome-Nilou Lab	RCV003231297	SCV002054964	likely pathogenic	Sotos syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Invitae	RCV003231297	SCV002136600	pathogenic	Sotos syndrome	2021-08-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 2017 of the NSD1 protein (p.Arg2017Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Sotos syndrome (PMID: 17565729, 27834868). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 159398). 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). This variant disrupts the p.Arg2017 amino acid residue in NSD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12807965, 15942875, 24412544, 26690673). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV003231297	SCV002577602	pathogenic	Sotos syndrome	2022-05-18	criteria provided, single submitter	clinical testing	PM1, PM2, PM5, PP2, PP3, PP5
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003231297	SCV002767016	pathogenic	Sotos syndrome	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Sotos syndrome (MIM#117550). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated SET domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals, some of which are reported de novo events, and is consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMIDs:12464997, 27834868, 30719864). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign