ClinVar Miner

Submissions for variant NM_022455.4(NSD1):c.6463G>A (p.Gly2155Arg) (rs1554206845)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521971 SCV000620159 likely pathogenic not provided 2017-08-25 criteria provided, single submitter clinical testing he G2155R variant in the NSD1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G2155R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and is located within the PHD-type 4 atypical zinc finger domain (Uniprot). In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on currently available evidence, we interpret G2155R as a likely pathogenic variant.
Invitae RCV001208873 SCV001380282 uncertain significance Beckwith-Wiedemann syndrome 2019-11-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2155 of the NSD1 protein (p.Gly2155Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 22 of the NSD1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NSD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 451457). 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"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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