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

gnomAD frequency: 0.00001  dbSNP: rs1017946059

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548054	SCV000626063	pathogenic	Ellis-van Creveld syndrome; Curry-Hall syndrome	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 206 of the EVC protein (p.Ser206Asn). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with EVC-related conditions (PMID: 19744229, 23220543; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 456000). 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. 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. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000673804	SCV000799048	likely pathogenic	Ellis-van Creveld syndrome	2018-04-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000673804	SCV003928721	pathogenic	Ellis-van Creveld syndrome	2023-04-28	criteria provided, single submitter	clinical testing	Variant summary: EVC c.617G>A (p.Ser206Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 247702 control chromosomes (gnomAD). c.617G>A has been reported in the literature in multiple individuals affected with Ellis-van Creveld syndrome (example: DAsdia_2013, UmmeKalsoom_2010). 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. The following publications have been ascertained in the context of this evaluation (PMID: 23220543, 19744229). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.