ClinVar Genomic variation as it relates to human health

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.

Variant summary: CUL7 c.3041T>G (p.Leu1014Arg) results in a non-conservative amino acid change located in the Cullin, N-terminal domain (IPR001373) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00016 in 251280 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CUL7 causing Three M Syndrome 1 (0.00016 vs 0.0011), allowing no conclusion about variant significance. c.3041T>G has been reported in the literature in multiple individuals affected with Three M Syndrome (Huber_2005, Huber_2009), including in a family with compound heterozygous individuals with a truncating variant. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and six classified it as pathogenic/likely pathogenic (one as uncertain significance). Based on the evidence outlined above, the variant was classified as pathogenic.

PM3_strong, PM2, PP3

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1014 of the CUL7 protein (p.Leu1014Arg). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 194657). This missense change has been observed in individual(s) with 3-M syndrome (PMID: 16142236, 19225462, 21396581; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs61752334, gnomAD 0.03%).

This variant is interpreted as likely pathogenic for 3M syndrome 1, based on the following ACMG criteria: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3_moderate; REVEL score 0.849). For recessive disorders, detected in trans with a pathogenic variant (PM3_strong; family 22 in PMID:16142236 and family 44 in PMID:19225462).

Reported as pathogenic in ClinVar but additional evidence is not available (ClinVar SCV000263029.3, SCV000226508.5; ClinVar); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16142236, 19225462, 34426522, 35982156)