Submissions for variant NM_014780.5(CUL7):c.3041T>G (p.Leu1014Arg)

gnomAD frequency: 0.00011  dbSNP: rs61752334

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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	2022-12-28	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported as pathogenic in ClinVar but additional evidence is not available (ClinVar SCV000263029.3, SCV000226508.5; ClinVar); This variant is associated with the following publications: (PMID: 16142236, 19225462, 34426522)
SIB Swiss Institute of Bioinformatics	RCV000755718	SCV000883195	uncertain significance	3M 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 (https://www.ncbi.nlm.nih.gov/pubmed/16142236).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000755718	SCV001369347	likely pathogenic	3M 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	likely pathogenic	not provided	2023-08-24	criteria provided, single submitter	clinical testing	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%).
Blueprint Genetics	RCV000480559	SCV001832415	pathogenic	not provided	2019-11-30	criteria provided, single submitter	clinical testing
Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics	RCV000755718	SCV002512101	pathogenic	3M syndrome 1	2022-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509281	SCV002819751	pathogenic	3-M syndrome	2022-12-22	criteria provided, single submitter	clinical testing	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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000755718	SCV004013283	likely pathogenic	3M syndrome 1	2023-06-08	criteria provided, single submitter	clinical testing	PM3_strong, PM2, PP3
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000480559	SCV001807894	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000480559	SCV001951046	pathogenic	not provided		no assertion criteria provided	clinical testing