Submissions for variant NM_014780.5(CUL7):c.2130_2131delinsTGCCTG (p.Cys711fs)

dbSNP: rs1554138553

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519666	SCV000619259	pathogenic	not provided	2017-07-19	criteria provided, single submitter	clinical testing	The c.2130_2131delCTinsTGCCTG variant in the CUL7 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codon Cysteine 711, changes this amino acid to an Alanine residue, and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Cys711AlafsX12. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2130_2131delCTinsTGCCTG variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.2130_2131delCTinsTGCCTG as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000519666	SCV004673044	pathogenic	not provided	2021-03-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with CUL7-related conditions. The frequency data for this variant in the population databases is not available, as this variant may be reported as separate entries in the ExAC database. This sequence change creates a premature translational stop signal (p.Cys711Alafs*12) in the CUL7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CUL7 are known to be pathogenic (PMID: 16142236, 17675530, 19225462).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767325	SCV005380655	pathogenic	3-M syndrome	2024-08-12	criteria provided, single submitter	clinical testing	Variant summary: CUL7 c.2130_2131delinsTGCCTG (p.Cys711AlafsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. It was identified as part of a in cis multinucleotide variant combination of c.2127_2129dupTGC and c.2132dupG in exon 9 of CUL7 gene . The specific variant was absent in 251004 control chromosomes. To our knowledge, no occurrence of c.2130_2131delinsTGCCTG in individuals affected with Three M Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. Loss of function variants in CUL7 gene are an established mechanism of disease. ClinVar contains an entry for this variant (Variation ID: 450651). Based on the evidence outlined above, the variant was classified as pathogenic.