ClinVar Miner

Submissions for variant NM_022455.4(NSD1):c.3549dup (p.Glu1184Ter) (rs797045813)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000192567 SCV000248323 pathogenic Sotos syndrome 1 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000414581 SCV000490674 pathogenic not provided 2018-08-15 criteria provided, single submitter clinical testing The c.3549dupT pathogenic variant in the NSD1 gene has been reported previously as c.3549-50insT in an individual with a Sotos-like phenotype who has some characteristics that are atypical of Sotos syndrome (Douglas et al., 2003). Additionally, c.3549dupT is reported as a pathogenic variant in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000248323.1; Landrum et al., 2016). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.3549dupT variant causes a frameshift starting with codon Glutamic acid 1184 and changes this amino acid to a premature Stop codon, denoted p.Glu1184Ter. The c.3549dupT variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Invitae RCV001231430 SCV001403951 pathogenic Beckwith-Wiedemann syndrome 2019-09-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1184*) in the NSD1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Sotos syndrome (PMID: 22924495, 15942875, 28475857). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 211726). Loss-of-function variants in NSD1 are known to be pathogenic (PMID: 12464997, 14571271, 15942875, 16247291). For these reasons, this variant has been classified as Pathogenic.

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