Submissions for variant NM_153717.3(EVC):c.617G>A (p.Ser206Asn) (rs1017946059)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000548054	SCV000626063	likely pathogenic	Ellis-van Creveld syndrome; Curry-Hall syndrome	2017-08-30	criteria provided, single submitter	clinical testing	This sequence change replaces serine with asparagine at codon 206 of the EVC protein (p.Ser206Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant also falls at the last nucleotide of exon 4 of the EVC coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Ellis-van Creveld syndrome in a single family (PMID: 19744229). The variant was homozygous in 3 affected siblings, while the unaffected parents were heterozygous carriers. This variant occurs with a likely pathogenic variant (p.Lys302del) in EVC in an individual with clinical features consistent with an EVC-related disease. Manual review of the sequencing data indicates that these two variants are on opposite chromosomes (in trans), which suggests the c.617G>A substitution may contribute to disease. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change at a consensus splice site that has been observed to segregate with disease and observed in trans with a likely pathogenic variant. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl	RCV000673804	SCV000799048	likely pathogenic	Ellis-van Creveld syndrome	2018-04-03	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000673804	SCV000916066	uncertain significance	Ellis-van Creveld syndrome	2018-10-19	criteria provided, single submitter	clinical testing	The EVC c.617G>A (p.Ser206Asn) missense variant has been reported in two studies and is found in a total of four individuals with Ellis-van Creveld syndrome, including in a homozygous state in three consanguineous siblings and in a compound heterozygous state with a canonical splice site variant in an unrelated individual (Umm-E-Kalsoom et al. 2010; D’Asdia et al. 2013). The p.Ser206Asn variant was absent from 200 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database in a region of good sequence coverage, and hence is presumed to be rare. Based on the limited evidence, the p.Ser206Asn variant is classified as a variant of unknown significance but suspicious for pathogenicity for Ellis-van Creveld syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.