ClinVar Miner

Submissions for variant NM_014780.5(CUL7):c.4391A>C (p.His1464Pro)

gnomAD frequency: 0.00001  dbSNP: rs121918229
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002281688 SCV002570865 pathogenic 3-M syndrome 2022-07-15 criteria provided, single submitter clinical testing Variant summary: CUL7 c.4391A>C (p.His1464Pro) results in a non-conservative amino acid change located in the N-terminal domain (IPR001373) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251450 control chromosomes (gnomAD). c.4391A>C has been reported in the literature in multiple families with homozygous individuals affected with Three M Syndrome 1 (Huber_2005, Huber_2009). These data indicate that the variant is very likely to be associated with disease. Several publications also reported experimental evidence evaluating an impact on protein function, and demonstrated severely decreased protein interactions, and ubiquitin ligase activities (Huber_2005, Li_2014, Yan_2014). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV004719608 SCV005325097 pathogenic not provided 2023-09-23 criteria provided, single submitter clinical testing Published functional studies found this variant is associated with significantly impaired ROC1 binding and reduced E3 ubiquitin ligase complex activity (PMID: 16142236); 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: 31589614, 21554755, 24793696, 16142236, 27173435, 23900270, 32235515, 19225462)
OMIM RCV000001681 SCV000021837 pathogenic 3M syndrome 1 2005-10-01 no assertion criteria provided literature only

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