ClinVar Miner

Submissions for variant NM_022455.4(NSD1):c.5431C>T (p.Arg1811Ter) (rs587784148)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000146875 SCV000194204 pathogenic Sotos syndrome 1 2013-02-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV000146875 SCV000807314 pathogenic Sotos syndrome 1 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 1-year-old male with global delay, downslanting palpebral fissures, hypertelorism, sparse hair, prominent forehead, progound hearing loss, overlapping toes, hypospadias, thin corpus callosum
Invitae RCV000805009 SCV000944951 pathogenic Beckwith-Wiedemann syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1811*) 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 individuals affected with or suspected of having an NSD1-related disorder (PMID: 16247291, 22924495) of whom it was found de novo in one individual (PMID: 12807965). ClinVar contains an entry for this variant (Variation ID: 159369). 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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000146875 SCV000996128 pathogenic Sotos syndrome 1 2018-04-13 criteria provided, single submitter clinical testing This variant is present in exon 16 of 23 and is therefore predicted to have a loss-of-function effect. NSD1 is loss-of-function intolerant (pLI=1) and haploinsufficiency is a well-established mechanism of disease. This variant has been previously reported in multiple individuals with Sotos syndrome (PMID: 15942875, 17565729, 16247291). It is absent from the ExAC and gnomAD population databases. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.5431C>T (p.Arg1811Ter) variant in NSD1 is classified as pathogenic.

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