ClinVar Miner

Submissions for variant NM_001007228.2(SPOP):c.362G>A (p.Arg121Gln)

dbSNP: rs2072157379
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
SIB Swiss Institute of Bioinformatics RCV001030767 SCV001432983 likely pathogenic Neurodevelopmental disorder with microcephaly and dysmorphic facies 2020-09-10 criteria provided, single submitter curation This variant is interpreted as likely pathogenic for Nabais Sa-de Vries syndrome 1, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); De novo (paternity and maternity confirmed) (PS2); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2). Well-established functional studies show a deleterious effect (PS3 downgraded to supporting).
Ambry Genetics RCV001265939 SCV001444111 likely pathogenic Inborn genetic diseases 2020-11-02 criteria provided, single submitter clinical testing The c.362G>A (p.R121Q) alteration is located in exon 7 (coding exon 4) of the SPOP gene. This alteration results from a G to A substitution at nucleotide position 362, causing the arginine (R) at amino acid position 121 to be replaced by a glutamine (Q). Based on data from the Genome Aggregation Database (gnomAD), the SPOP c.362G>A alteration was not observed, with coverage at this position. The SPOP c.362G>A (p.R121Q) alteration was observed de novo in a patient with congenital microcephaly, sensorineural hearing loss, mild intellectual disability, behavioral abnormalities, and craniofacial dysmorphisms including a small forehead, highly arched eyebrows, blepharophimosis, a full nasal tip, flat philtrum, micrognathia, and a pointed chin (Nabais Sá, 2020). The p.R121 amino acid is conserved in available vertebrate species. The in silico prediction for the p.R121Q alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
GeneDx RCV002272391 SCV002558573 pathogenic not provided 2022-01-13 criteria provided, single submitter clinical testing Published functional studies indicate that the variant results in reduced BET expression through a gain-of-function mechanism (Nabais et al., 2020; Janouskova et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31026449, 25766326, 28805821, 32109420)
OMIM RCV001030767 SCV001194275 pathogenic Neurodevelopmental disorder with microcephaly and dysmorphic facies 2020-05-01 no assertion criteria provided literature only

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