ClinVar Miner

Submissions for variant NM_147127.5(EVC2):c.222_228+21del

dbSNP: rs1484464278
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV001449812 SCV001653105 likely pathogenic Ellis-van Creveld syndrome 2020-06-09 criteria provided, single submitter clinical testing The c.222_228+21del variant in EVC2 has not been reported in individuals with Ellis-van Creveld syndrome but has been identified in 1/15414 of European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). This variant is a deletion of 27 nucleotides that encompasses the 5' canonical splice site (+/- 1,2) (exon1 in NM_147127.4) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the EVC2 gene is an established disease mechanism in autosomal recessive Ellis-van Creveld syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Ellis-van Creveld syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PM2
Invitae RCV002557520 SCV003498509 likely pathogenic Ellis-van Creveld syndrome; Curry-Hall syndrome 2023-04-08 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1120123). This variant has not been reported in the literature in individuals affected with EVC2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant results in the deletion of part of exon 1 (c.222_228+21del) of the EVC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EVC2 are known to be pathogenic (PMID: 17024374, 19810119, 19876929).

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