ClinVar Miner

Submissions for variant NM_022455.4(NSD1):c.3215G>A (p.Arg1072Gln) (rs28932180)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000719553 SCV000850422 likely benign History of neurodevelopmental disorder 2017-05-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,In silico models in agreement (benign),Does not segregate with disease in family study (genes with incomplete penetrance)
GeneDx RCV000522991 SCV000617890 uncertain significance not specified 2015-11-10 criteria provided, single submitter clinical testing The R1072Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project reports R1072Q was observed in 2/4406 (0.04%) alleles from individuals of African background, indicating it may be a rare variant in this population. The variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000698123 SCV000826766 uncertain significance Beckwith-Wiedemann syndrome 2018-05-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1072 of the NSD1 protein (p.Arg1072Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs28932180, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with NSD1-related disease. ClinVar contains an entry for this variant (Variation ID: 449587). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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