ClinVar Miner

Submissions for variant NM_022455.5(NSD1):c.5741G>A (p.Arg1914His)

dbSNP: rs587784155
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001771025 SCV001994019 uncertain significance not provided 2019-07-01 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
3billion RCV003232400 SCV002521335 likely pathogenic Sotos syndrome 2022-05-22 criteria provided, single submitter clinical testing The variant is absent from the gnomAD v2.1.1 dataset. Different pathogenic amino acid change has been reported with sufficient evidence at the same codon (ClinVar ID: VCV000159375,VCV000159376,PMID:15452385). In silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure/function (REVEL: 0.817>=0.6, 3CNET: 0.998>=0.75). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp RCV001771025 SCV005798967 likely pathogenic not provided 2023-04-27 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1914 of the NSD1 protein (p.Arg1914His). This missense change has been observed in individual(s) with clinical features of Sotos syndrome (Invitae). 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. This variant disrupts the p.Arg1914 amino acid residue in NSD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15452385, 17565729; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1306845).

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