ClinVar Miner

Submissions for variant NM_022455.4(NSD1):c.5020del (p.Cys1674fs) (rs1581468355)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000814290 SCV000954693 pathogenic Beckwith-Wiedemann syndrome 2018-11-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys1674Alafs*61) 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 to be de novo in an individual affected with Sotos syndrome (PMID: 17565729). 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.
GeneDx RCV001008806 SCV001168606 pathogenic not provided 2018-08-23 criteria provided, single submitter clinical testing The c.5020delT variant in the NSD1 gene has been reported previously as an apparently de novo variant in association with Sotos syndrome (Saugier-Veber et al., 2007). The deletion causes a frameshift starting with codon Cystine 1674, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 61 of the new reading frame, denoted p.Cys1674AlafsX61. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is not observed in large population cohorts (Lek et al., 2016). We consider this variant to be pathogenic, and its presence is consistent with a molecular diagnosis in this patient.

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