ClinVar Miner

Submissions for variant NM_014780.4(CUL7):c.3041T>G (p.Leu1014Arg) (rs61752334)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000480559 SCV000226508 likely pathogenic not provided 2015-05-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000210570 SCV000263029 likely pathogenic Inborn genetic diseases 2014-03-10 criteria provided, single submitter clinical testing
GeneDx RCV000480559 SCV000564918 likely pathogenic not provided 2018-05-02 criteria provided, single submitter clinical testing The L1014R variant in the CUL7 gene has been previously reported in either the homozygous state or in the heterozygous state with a second identified CUL7 variant in patients with 3-M syndrome (Huber et al., 2005; Huber et al., 2009). The L1014R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L1014R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret L1014R as a likely pathogenic variant.
SIB Swiss Institute of Bioinformatics RCV000755718 SCV000883195 uncertain significance Three M syndrome 1 2018-10-15 criteria provided, single submitter curation This variant is interpreted as Uncertain Significance - Insufficient Evidence, for Three M syndrome 1, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3-Supporting => PM3 downgraded in strength to Supporting (
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000755718 SCV001369347 likely pathogenic Three M syndrome 1 2019-12-12 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. This variant was detected in homozygous state.
Invitae RCV000480559 SCV001531226 uncertain significance not provided 2020-07-28 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 1014 of the CUL7 protein (p.Leu1014Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is present in population databases (rs61752334, ExAC 0.04%). This variant has been observed in individual(s) with 3-M syndrome (PMID: 16142236, 19225462, 21396581). ClinVar contains an entry for this variant (Variation ID: 194657). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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