Submissions for variant NM_147127.5(EVC2):c.3659+2T>C

gnomAD frequency: 0.00003  dbSNP: rs200300612

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000665483	SCV000449971	likely pathogenic	Ellis-van Creveld syndrome	2016-09-18	criteria provided, single submitter	clinical testing	The EVC2 c.3659+2T>C variant, also known as IVS21+2T>C, occurs in a canonical splice donor site and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in three studies in which it is found in a total of three individuals with Ellis-van Creveld syndrome, all in a compound heterozygous state with truncating variants on the second allele (Tompson et al. 2007; Sund et al. 2009; D'Asdia et al. 2013). The c.3659+2T>C variant was absent from 400 control chromosomes and is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of splice donor variants, the c.3659+2T>C variant is classified as likely pathogenic for Ellis-van Creveld syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000521259	SCV000617820	pathogenic	not provided	2021-05-25	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion/insertion of a critical region; This variant is associated with the following publications: (PMID: 25525159, 19876929, 23220543, 19251731, 17024374, 31589614)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695869	SCV000824393	pathogenic	Ellis-van Creveld syndrome; Curry-Hall syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 21 of the EVC2 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs200300612, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with Ellis-van Creveld syndrome (PMID: 17024374, 23220543; Invitae). ClinVar contains an entry for this variant (Variation ID: 348980). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the EVC2 protein in which other variant(s) (p.Ser1220Argfs*3) have been determined to be pathogenic (PMID: 12571802, 17024374, 19810119, 23220543). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000521259	SCV002022224	pathogenic	not provided	2020-03-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003922532	SCV004749163	pathogenic	EVC2-related disorder	2023-12-30	criteria provided, single submitter	clinical testing	The EVC2 c.3659+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in multiple individuals with Ellis-van Creveld syndrome (Tompson et al. 2007. PubMed ID: 17024374; Sund et al. 2009. PubMed ID: 19251731; D'Asdia et al. 2013. PubMed ID: 23220543). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in EVC2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Counsyl	RCV000665483	SCV000789613	pathogenic	Ellis-van Creveld syndrome	2017-02-13	no assertion criteria provided	clinical testing